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1
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Angelova DM, Tsolova A, Prater M, Ballasy N, Bacon W, Hamilton RS, Blackwell D, Yu Z, Li X, Liu X, Hemberger M, Charnock-Jones DS. Single-cell RNA sequencing identifies CXADR as a fate determinant of the placental exchange surface. Nat Commun 2025; 16:142. [PMID: 39747179 PMCID: PMC11695997 DOI: 10.1038/s41467-024-55597-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 12/16/2024] [Indexed: 01/04/2025] Open
Abstract
The placenta is the critical interface between mother and fetus, and consequently, placental dysfunction underlies many pregnancy complications. Placental formation requires an adequate expansion of trophoblast stem and progenitor cells followed by finely tuned lineage specification events. Here, using single-cell RNA sequencing of mouse trophoblast stem cells during the earliest phases of differentiation, we identify gatekeepers of the stem cell state, notably Nicol1, and uncover unsuspected trajectories of cell lineage diversification as well as regulators of lineage entry points. We show that junctional zone precursors and precursors of one of the two syncytial layers of the mouse placental labyrinth, the Syncytiotrophoblast-I lineage, initially share similar trajectories. Importantly, our functional analysis of one such lineage precursor marker, CXADR, demonstrates that this cell surface protein regulates the differentiation dynamics between the two syncytial layers of the mouse labyrinth, ensuring the correct establishment of the placental exchange surface. Deciphering the mechanisms underlying trophoblast lineage specification will inform our understanding of human pregnancy in health and disease.
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Affiliation(s)
- Dafina M Angelova
- Department of Obstetrics and Gynaecology, University of Cambridge, NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- Loke Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Aleksandra Tsolova
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada
| | - Malwina Prater
- Loke Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom
- Functional Genomics Centre, Cancer Research Horizons, Milner Therapeutics Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom
| | - Noura Ballasy
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada
| | - Wendi Bacon
- Loke Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom
- School of Life, Health & Chemical Sciences, The Open University, Milton Keynes, United Kingdom
| | - Russell S Hamilton
- Loke Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Danielle Blackwell
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada
| | - Ziyi Yu
- College of Chemical Engineering, Nanjing Tech University, Nanjing, People's Republic of China
| | - Xin Li
- Sphere Fluidics Ltd., Building One, Granta Centre, Granta Park, Great Abington, Cambridge, England, United Kingdom
| | - Xin Liu
- Sphere Fluidics Ltd., Building One, Granta Centre, Granta Park, Great Abington, Cambridge, England, United Kingdom
| | - Myriam Hemberger
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada.
- Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada.
| | - D Stephen Charnock-Jones
- Department of Obstetrics and Gynaecology, University of Cambridge, NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
- Loke Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
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2
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Ballasy N, Apantaku I, Dean W, Hemberger M. Off to a good start: The importance of the placental exchange surface - Lessons from the mouse. Dev Biol 2025; 517:248-264. [PMID: 39491740 DOI: 10.1016/j.ydbio.2024.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/04/2024] [Accepted: 10/31/2024] [Indexed: 11/05/2024]
Abstract
The role of the chorio-allantoic placenta as the critical nutrient- and oxygen-supplying organ to nourish the demands of the fetus has been well recognized. This function relies on the successful establishment of the placental feto-maternal exchange unit, or interhaemal barrier, across which all nutrients as well as waste products must pass to cross from the maternal to the fetal blood circulation, or vice versa, respectively. As a consequence, defects in the establishment of this elaborate interface lead to fetal growth retardation or even embryonic lethality, depending on the severity of the defect. Beyond this essential role, however, it has also emerged that the functionality of the feto-maternal interface dictates the proper development of specific embryonic organs, with tightest links observed to the formation of the heart. In this article, we build on the foundational strength of the mouse as experimental model in which the placental causality of embryonic defects can be genetically proven. We discuss in detail the formation of the interhaemal barrier that makes up the labyrinth layer of the murine placenta, including insights into drivers of its formation and the interdependence of the cell types that make up this essential interface, from in vivo and in vitro data using mouse trophoblast stem cells. We highlight mouse genetic tools that enable the elucidation of cause-effect relationships between defects driven by either the trophoblast cells of the placenta or by embryonic cell types. We specifically emphasize gene knockouts for which a placental causality of embryonic heart defects has been demonstrated. This in-depth perspective provides much-needed insights while highlighting remaining gaps in knowledge that are essential for gaining a better understanding of the multi-facetted roles of the placenta in setting us up for a healthy start in life well beyond nutritional support alone.
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Affiliation(s)
- Noura Ballasy
- Dept. of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Ifeoluwa Apantaku
- Dept. of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Wendy Dean
- Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Dept. of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Myriam Hemberger
- Dept. of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.
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3
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Wu S, Liu K, Cui Y, Zhou B, Zhao H, Xiao X, Zhou Q, Ma D, Li X. N6-methyladenosine dynamics in placental development and trophoblast functions, and its potential role in placental diseases. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167290. [PMID: 38866113 DOI: 10.1016/j.bbadis.2024.167290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 06/02/2024] [Accepted: 06/06/2024] [Indexed: 06/14/2024]
Abstract
N6-methyladenosine (m6A) is the most abundant modification controlling RNA metabolism and cellular functions, but its roles in placental development are still poorly understood. Here, we characterized the synchronization of m6A modifications and placental functions by mapping the m6A methylome in human placentas (n = 3, each trimester), revealing that the dynamic patterns of m6A were associated with gene expression homeostasis and different biological pathways in placental development. Then, we generated trophoblast-specific knockout mice of Wtap, a critical component of methyltransferase complex, and demonstrated that Wtap was essential for trophoblast proliferation, placentation and perinatal growth. Further in vitro experiments which includes cell viability assays and series molecular binding assays demonstrated that WTAP-m6A-IGF2BP3 axis regulated the RNA stability and translation of Anillin (ANLN) and VEGFA, promoting trophoblast proliferation and secretion. Dysregulation of this regulatory axis was observed in placentas from pregnancies with fetal growth restriction (FGR) or preeclampsia, revealing the pathogenic effects of imbalanced m6A modifications. Therefore, our findings provide novel insights into the functions and regulatory mechanisms of m6A modifications in placental development and placental-related gestational diseases.
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Affiliation(s)
- Suwen Wu
- Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Ketong Liu
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Yutong Cui
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Bingyan Zhou
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, China
| | - Huanqiang Zhao
- Shenzhen Maternity and Children Health Care Hospital, Shenzhen, China
| | - Xirong Xiao
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Qiongjie Zhou
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
| | - Duan Ma
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
| | - Xiaotian Li
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China; Shenzhen Maternity and Children Health Care Hospital, Shenzhen, China.
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4
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Miki R, Matsuo S, Ushida T, Tano S, Imai K, Nawa A, Kajiyama H, Kotani T. TJP1 suppresses trophoblast cell invasion by expressing E2F8 in the human placenta. Mol Cell Endocrinol 2024; 591:112277. [PMID: 38795825 DOI: 10.1016/j.mce.2024.112277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 05/20/2024] [Accepted: 05/22/2024] [Indexed: 05/28/2024]
Abstract
Adequate extravillous trophoblast (EVT) invasion into the maternal decidua is important for human placental development. We identified that E2F transcription factor 8 (E2F8) suppresses EVT invasion, and that tight junction protein-1 (TJP1) is a potential downstream target gene of E2F8. We investigated the role of TJP1 in the human placenta and regulation of TJP1 expression by E2F8. TJP1 expression decreased in E2F8 knockdown HTR-8/SVneo cells. TJP1 and E2F8 were co-expressed in villi in the first-trimester placenta and in EVTs and villi in the third-trimester placenta. TJP1 was significantly increased in the pre-eclamptic compared with control placenta. TJP1 knockdown increased the invasion of HTR-8/SVneo cells, while TJP1 overexpression inhibited cell invasion. Halo-E2F8 overexpression significantly increased TJP1 expression and TJP1 transcription compared with control placenta. Our findings suggest that E2F8 promotes TJP1 transcription, and that TJP1 expression by E2F8 inhibits EVT invasion. TJP1 and E2F8 may be related to pre-eclampsia pathogenesis.
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Affiliation(s)
- Rika Miki
- Laboratory of Bell Research Center Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan.
| | - Seiko Matsuo
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan
| | - Takafumi Ushida
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan; Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Aichi, 466-8560, Japan
| | - Sho Tano
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan
| | - Kenji Imai
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan
| | - Akihiro Nawa
- Laboratory of Bell Research Center Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan
| | - Tomomi Kotani
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan; Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Aichi, 466-8560, Japan.
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5
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Wang J, Zhou X, Han T, Zhang H. Epigenetic signatures of trophoblast lineage and their biological functions. Cells Dev 2024; 179:203934. [PMID: 38942294 DOI: 10.1016/j.cdev.2024.203934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 03/13/2024] [Accepted: 06/13/2024] [Indexed: 06/30/2024]
Abstract
Trophoblasts play a crucial role in embryo implantation and in interacting with the maternal uterus. The trophoblast lineage develops into a substantial part of the placenta, a temporary extra-embryonic organ, capable of undergoing distinctive epigenetic events during development. The critical role of trophoblast-specific epigenetic signatures in regulating placental development has become known, significantly advancing our understanding of trophoblast identity and lineage development. Scientific efforts are revealing how trophoblast-specific epigenetic signatures mediate stage-specific gene regulatory programming during the development of the trophoblast lineage. These epigenetic signatures have a significant impact on blastocyst formation, placental development, as well as the growth and survival of embryos and fetuses. In evolution, DNA hypomethylation in the trophoblast lineage is conserved, and there is a significant disparity in the control of epigenetic dynamics and the landscape of genomic imprinting. Scientists have used murine and human multipotent trophoblast cells as in vitro models to recapitulate the essential epigenetic processes of placental development. Here, we review the epigenetic signatures of the trophoblast lineage and their biological functions to enhance our understanding of placental evolution, development, and function.
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Affiliation(s)
- Jianqi Wang
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xiaobo Zhou
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Reproductive Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Tingli Han
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, 400016, China; The Center for Reproductive Medicine, Obstetrics and Gynecology Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
| | - Hua Zhang
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, 400016, China.
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6
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Darmasaputra GS, Geerlings CC, Chuva de Sousa Lopes SM, Clevers H, Galli M. Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase. J Cell Biol 2024; 223:e202403020. [PMID: 38727809 PMCID: PMC11090133 DOI: 10.1083/jcb.202403020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/24/2024] [Accepted: 04/26/2024] [Indexed: 05/15/2024] Open
Abstract
Binucleated polyploid cells are common in many animal tissues, where they arise by endomitosis, a non-canonical cell cycle in which cells enter M phase but do not undergo cytokinesis. Different steps of cytokinesis have been shown to be inhibited during endomitosis M phase in rodents, but it is currently unknown how human cells undergo endomitosis. In this study, we use fetal-derived human hepatocyte organoids (Hep-Orgs) to investigate how human hepatocytes initiate and execute endomitosis. We find that cells in endomitosis M phase have normal mitotic timings, but lose membrane anchorage to the midbody during cytokinesis, which is associated with the loss of four cortical anchoring proteins, RacGAP1, Anillin, SEPT9, and citron kinase (CIT-K). Moreover, reduction of WNT activity increases the percentage of binucleated cells in Hep-Orgs, an effect that is dependent on the atypical E2F proteins, E2F7 and E2F8. Together, we have elucidated how hepatocytes undergo endomitosis in human Hep-Orgs, providing new insights into the mechanisms of endomitosis in mammals.
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Affiliation(s)
- Gabriella S. Darmasaputra
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, Netherlands
| | - Cindy C. Geerlings
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, Netherlands
| | | | - Hans Clevers
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Matilde Galli
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, Netherlands
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Karan D, Dubey S, Gunewardena S, Iczkowski KA, Singh M, Liu P, Poletti A, Choo Y, Chen H, Hamann MT. Manzamine A reduces androgen receptor transcription and synthesis by blocking E2F8-DNA interactions and effectively inhibits prostate tumor growth in mice. Mol Oncol 2024; 18:1966-1979. [PMID: 38605607 PMCID: PMC11306517 DOI: 10.1002/1878-0261.13637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 02/14/2024] [Accepted: 03/12/2024] [Indexed: 04/13/2024] Open
Abstract
The androgen receptor (AR) is the main driver in the development of castration-resistant prostate cancer, where the emergence of AR splice variants leads to treatment-resistant disease. Through detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F8 as a previously unknown regulator of AR transcription that prevents AR synthesis in prostate cancer cells. MA significantly inhibited the growth of various prostate cancer cell lines and was highly effective in inhibiting xenograft tumor growth in mice without any pathophysiological perturbations in major organs. MA suppressed the full-length AR (AR-FL), its spliced variant AR-V7, and the AR-regulated prostate-specific antigen (PSA; also known as KLK3) and human kallikrein 2 (hK2; also known as KLK2) genes. RNA sequencing (RNA-seq) analysis and protein modeling studies revealed E2F8 interactions with DNA as a potential novel target of MA, suppressing AR transcription and its synthesis. This novel mechanism of blocking AR biogenesis via E2F8 may provide an opportunity to control therapy-resistant prostate cancer over the currently used AR antagonists designed to target different parts of the AR gene.
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Affiliation(s)
- Dev Karan
- Department of Pathology, and MCW Cancer CenterMedical College of WisconsinMilwaukeeWIUSA
| | - Seema Dubey
- Department of Pathology, and MCW Cancer CenterMedical College of WisconsinMilwaukeeWIUSA
| | - Sumedha Gunewardena
- Department of Cell Biology and PhysiologyUniversity of Kansas Medical CenterKSUSA
| | - Kenneth A. Iczkowski
- Department of Pathology, and MCW Cancer CenterMedical College of WisconsinMilwaukeeWIUSA
| | - Manohar Singh
- Department of Pathology, and MCW Cancer CenterMedical College of WisconsinMilwaukeeWIUSA
| | - Pengyuan Liu
- Department of Physiology and Center of Systems Molecular MedicineMedical College of WisconsinMilwaukeeWIUSA
| | - Angelo Poletti
- Department of Pharmacological and Biomolecular SciencesUniversity of MilanItaly
| | - Yeun‐Mun Choo
- Department of ChemistryUniversity of MalayaKuala LumpurMalaysia
| | - Hui‐Zi Chen
- Department of MedicineMedical College of WisconsinMilwaukeeWIUSA
| | - Mark T. Hamann
- Department of Drug Discovery and Biomedical Sciences and Public Health, Colleges of Pharmacy and Medicine, Hollings Cancer CenterMedical University of South CarolinaCharlestonSCUSA
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8
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Home P, Ghosh A, Kumar RP, Ray S, Gunewardena S, Kumar R, Dasgupta P, Roy N, Saha A, Ouseph MM, Leone GW, Paul S. A Single Trophoblast Layer Acts as the Gatekeeper at the Endothelial-Hematopoietic Crossroad in the Placenta. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.12.603303. [PMID: 39071312 PMCID: PMC11275844 DOI: 10.1101/2024.07.12.603303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
During embryonic development the placental vasculature acts as a major hematopoietic niche, where endothelial to hematopoietic transition ensures emergence of hematopoietic stem cells (HSCs). However, the molecular mechanisms that regulate the placental hematoendothelial niche are poorly understood. Using a parietal trophoblast giant cell (TGC)-specific knockout mouse model and single-cell RNA-sequencing, we show that the paracrine factors secreted by the TGCs are critical in the development of this niche. Disruptions in the TGC-specific paracrine signaling leads to the loss of HSC population and the concomitant expansion of a KDR+/DLL4+/PROM1+ hematoendothelial cell-population in the placenta. Combining single-cell transcriptomics and receptor-ligand pair analyses, we also define the parietal TGC-dependent paracrine signaling network and identify Integrin signaling as a fundamental regulator of this process. Our study elucidates novel mechanisms by which non-autonomous signaling from the primary parietal TGCs maintain the delicate placental hematopoietic-angiogenic balance and ensures embryonic and extraembryonic development.
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Affiliation(s)
- Pratik Home
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Present address: XenoTech, A BioIVT Company, 1101 W Cambridge Cir Dr, Kansas City, KS 66103
| | - Ananya Ghosh
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Present address: Department of Urology, University of California San Francisco, 35, Medical 12 Center Way, San Francisco, CA 94143
| | - Ram Parikshan Kumar
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Institute for Reproductive Health and Perinatal Research, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Soma Ray
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Rajnish Kumar
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Purbasa Dasgupta
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Namrata Roy
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Abhik Saha
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Madhu M. Ouseph
- Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065
| | - Gustavo W. Leone
- Department of Biochemistry, Medical College of Wisconsin, WI 53226, USA
| | - Soumen Paul
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Institute for Reproductive Health and Perinatal Research, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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9
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Yang N, Sun Y, Han B, Deng N, Li G, Han Q, Wang Y, Cai H, Liu F, Cao B, Deng W, Bao H, Kong S, Lu J, Wang H. Trophoblastic signals facilitate endometrial interferon response and lipid metabolism, ensuring normal decidualization. Cell Rep 2024; 43:114246. [PMID: 38762885 DOI: 10.1016/j.celrep.2024.114246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 04/04/2024] [Accepted: 05/02/2024] [Indexed: 05/21/2024] Open
Abstract
The decidua plays a crucial role in providing structural and trophic support to the developing conceptus before placentation. Following embryo attachment, embryonic components intimately interact with the decidual tissue. While evidence indicates the participation of embryo-derived factors in crosstalk with the uterus, the extent of their impact on post-implantation decidual development requires further investigation. Here, we utilize transgenic mouse models to selectively eliminate primary trophoblast giant cells (pTGCs), the embryonic cells that interface with maternal tissue at the forefront. pTGC ablation impairs decidualization and compromises decidual interferon response and lipid metabolism. Mechanistically, pTGCs release factors such as interferon kappa (IFNK) to strengthen the decidual interferon response and lipoprotein lipase (LPL) to enhance lipid accumulation within the decidua, thereby promoting decidualization. This study presents genetic and metabolomic evidence reinforcing the proactive role of pTGC-derived factors in mobilizing maternal resources to strengthen decidualization, facilitating the normal progression of early pregnancy.
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Affiliation(s)
- Ningjie Yang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Yang Sun
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Bing Han
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Na Deng
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Gaizhen Li
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Qian Han
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Yinan Wang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Han Cai
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Fan Liu
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Bin Cao
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Wenbo Deng
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Haili Bao
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
| | - Shuangbo Kong
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
| | - Jinhua Lu
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
| | - Haibin Wang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
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10
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Liu Z, Wang C, Tang Y, Zhang X, Pei J, Liu H, Yu Y, Gu W. ENO1 promotes trophoblast invasion regulated by E2F8 in recurrent miscarriage. FASEB J 2024; 38:e23631. [PMID: 38661062 DOI: 10.1096/fj.202302032rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 04/06/2024] [Accepted: 04/12/2024] [Indexed: 04/26/2024]
Abstract
Recurrent miscarriage (RM) is related to the dysfunction of extravillous trophoblast cells (EVTs), but the comprehensive mechanisms remain largely unexplored. We analyzed single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing and microarray datasets obtained from Gene Expression Omnibus (GEO) database to explore the hub genes in the mechanisms of RM. We identified 1724 differentially expressed genes (DEGs) in EVTs from the RM, and they were all expressed along the trajectory of EVTs. These DEGs were associated with hypoxia and glucose metabolism. Single-cell Regulatory Network Inference and Clustering (SCENIC) analysis revealed that E2F transcription factor (E2F) 8 (E2F8) was a key transcription factor for these DEGs. And the expression of ENO1 can be positively regulated by E2F8 via RNA sequencing analysis. Subsequently, we performed immunofluorescence assay (IF), plasmid transfection, western blotting, chromatin immunoprecipitation (ChIP), real-time quantitative polymerase chain reaction (qRT-PCR), and transwell assays for validation experiments. We found that the expression of alpha-Enolase 1 (ENO1) was lower in the placentas of RM. Importantly, E2F8 can transcriptionally regulate the expression of ENO1 to promote the invasion of trophoblast cells by inhibiting secreted frizzled-related protein 1/4 (SFRP1/4) to activate Wnt signaling pathway. Our results suggest that ENO1 can promote trophoblast invasion via an E2F8-dependent manner, highlighting a potential novel target for the physiological mechanisms of RM.
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Affiliation(s)
- Zhenzhen Liu
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Chengjie Wang
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Yao Tang
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Xiaoyue Zhang
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Jiangnan Pei
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Haiyan Liu
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Yi Yu
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Weirong Gu
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
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11
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Iqbal K, Dominguez EM, Nixon B, Moreno-Irusta A, Crnkovich B, Scott RL, Vu HTH, Tuteja G, Vivian JL, Soares MJ. Conditionally mutant animal model for investigating the invasive trophoblast cell lineage. Development 2024; 151:dev202239. [PMID: 38112206 PMCID: PMC10820817 DOI: 10.1242/dev.202239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 12/11/2023] [Indexed: 12/21/2023]
Abstract
Placental development involves coordinated expansion and differentiation of trophoblast cell lineages possessing specialized functions. Among the differentiated trophoblast cell lineages are invasive trophoblast cells, which exit the placenta and invade the uterus, where they restructure the uterine parenchyma and facilitate remodeling of uterine spiral arteries. The rat exhibits deep intrauterine trophoblast cell invasion, a feature shared with human placentation, and is also amenable to gene manipulation using genome-editing techniques. In this investigation, we generated a conditional rat model targeting the invasive trophoblast cell lineage. Prolactin family 7, subfamily b, member 1 (Prl7b1) is uniquely and abundantly expressed in the rat invasive trophoblast cell lineage. Disruption of Prl7b1 did not adversely affect placental development. We demonstrated that the Prl7b1 locus could be effectively used to drive the expression of Cre recombinase in invasive trophoblast cells. Our rat model represents a new tool for investigating candidate genes contributing to the regulation of invasive trophoblast cells and their roles in trophoblast-guided uterine spiral artery remodeling.
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Affiliation(s)
- Khursheed Iqbal
- Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Esteban M. Dominguez
- Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Brandon Nixon
- Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Ayelen Moreno-Irusta
- Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Benjamin Crnkovich
- Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Regan L. Scott
- Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Ha T. H. Vu
- Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011, USA
- Bioinformatics and Computational Biology Interdepartmental Graduate Program, Iowa State University, Ames, IA 50011, USA
| | - Geetu Tuteja
- Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011, USA
- Bioinformatics and Computational Biology Interdepartmental Graduate Program, Iowa State University, Ames, IA 50011, USA
| | - Jay L. Vivian
- Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Division of Clinical Genetics, Department of Pediatrics, Children's Mercy Research Institute, Children's Mercy Kansas City, Kansas City, MO 64018, USA
| | - Michael J. Soares
- Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Center for Perinatal Research, Children's Mercy Research Institute, Children's Mercy Kansas City, Kansas City, MO 64108, USA
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12
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Zhang L, Zhang S, Yuan M, Zhan F, Song M, Shang P, Yang F, Li X, Qiao R, Han X, Li X, Fang M, Wang K. Genome-Wide Association Studies and Runs of Homozygosity to Identify Reproduction-Related Genes in Yorkshire Pig Population. Genes (Basel) 2023; 14:2133. [PMID: 38136955 PMCID: PMC10742578 DOI: 10.3390/genes14122133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/10/2023] [Accepted: 11/19/2023] [Indexed: 12/24/2023] Open
Abstract
Reproductive traits hold considerable economic importance in pig breeding and production. However, candidate genes underpinning the reproductive traits are still poorly identified. In the present study, we executed a genome-wide association study (GWAS) and runs of homozygosity (ROH) analysis using the PorcineSNP50 BeadChip array for 585 Yorkshire pigs. Results from the GWAS identified two genome-wide significant and eighteen suggestive significant single nucleotide polymorphisms (SNPs) associated with seven reproductive traits. Furthermore, we identified candidate genes, including ELMO1, AOAH, INSIG2, NUP205, LYPLAL1, RPL34, LIPH, RNF7, GRK7, ETV5, FYN, and SLC30A5, which were chosen due to adjoining significant SNPs and their functions in immunity, fertilization, embryonic development, and sperm quality. Several genes were found in ROH islands associated with spermatozoa, development of the fetus, mature eggs, and litter size, including INSL6, TAF4B, E2F7, RTL1, CDKN1C, and GDF9. This study will provide insight into the genetic basis for pig reproductive traits, facilitating reproduction improvement using the marker-based selection methods.
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Affiliation(s)
- Lige Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; (L.Z.); (S.Z.); (M.Y.); (F.Z.); (M.S.); (F.Y.); (X.L.); (R.Q.); (X.H.); (X.L.)
| | - Songyuan Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; (L.Z.); (S.Z.); (M.Y.); (F.Z.); (M.S.); (F.Y.); (X.L.); (R.Q.); (X.H.); (X.L.)
| | - Meng Yuan
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; (L.Z.); (S.Z.); (M.Y.); (F.Z.); (M.S.); (F.Y.); (X.L.); (R.Q.); (X.H.); (X.L.)
| | - Fengting Zhan
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; (L.Z.); (S.Z.); (M.Y.); (F.Z.); (M.S.); (F.Y.); (X.L.); (R.Q.); (X.H.); (X.L.)
| | - Mingkun Song
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; (L.Z.); (S.Z.); (M.Y.); (F.Z.); (M.S.); (F.Y.); (X.L.); (R.Q.); (X.H.); (X.L.)
| | - Peng Shang
- Animal Science College, Tibet Agriculture and Animal Husbandry University, Linzhi 860000, China;
| | - Feng Yang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; (L.Z.); (S.Z.); (M.Y.); (F.Z.); (M.S.); (F.Y.); (X.L.); (R.Q.); (X.H.); (X.L.)
| | - Xiuling Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; (L.Z.); (S.Z.); (M.Y.); (F.Z.); (M.S.); (F.Y.); (X.L.); (R.Q.); (X.H.); (X.L.)
| | - Ruimin Qiao
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; (L.Z.); (S.Z.); (M.Y.); (F.Z.); (M.S.); (F.Y.); (X.L.); (R.Q.); (X.H.); (X.L.)
| | - Xuelei Han
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; (L.Z.); (S.Z.); (M.Y.); (F.Z.); (M.S.); (F.Y.); (X.L.); (R.Q.); (X.H.); (X.L.)
| | - Xinjian Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; (L.Z.); (S.Z.); (M.Y.); (F.Z.); (M.S.); (F.Y.); (X.L.); (R.Q.); (X.H.); (X.L.)
| | - Meiying Fang
- Department of Animal Genetics and Breeding, National Engineering Laboratory for Animal Breeding, MOA Laboratory of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Kejun Wang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; (L.Z.); (S.Z.); (M.Y.); (F.Z.); (M.S.); (F.Y.); (X.L.); (R.Q.); (X.H.); (X.L.)
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13
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Anamthathmakula P, Shallie PD, Nayak N, Dhal S, Vivian JL, Mor G, Soares MJ, Nayak NR. Variable Cre Recombination Efficiency in Placentas of Cyp19-Cre ROSA mT/mG Transgenic Mice. Cells 2023; 12:2096. [PMID: 37626906 PMCID: PMC10453067 DOI: 10.3390/cells12162096] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/06/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
The aromatase-Cre recombinase (Cyp19-Cre) transgenic mouse model has been extensively used for placenta-specific gene inactivation. In a pilot study, we observed unexpected phenotypes using this mouse strain, which prompted an extensive characterization of Cyp19-Cre placental phenotypes using ROSAmT/mG transgenic reporter mice. The two strains were mated to generate bi-transgenic Cyp19-Cre;ROSAmT/mG mice following a standard transgenic breeding scheme, and placental and fetal tissues were analyzed on embryonic day 17.5. Both maternal and paternal Cre inheritance were analyzed by mating the respective Cyp19-Cre and ROSAmT/mG males and females. The genotype results showed the expected percentage of Cyp19-Cre;ROSAmT/mG fetuses (73%) and Cre mRNA was expressed in all of the Cyp19-Cre placentas. However, surprisingly, only about 50% of the Cyp19-Cre;ROSAmT/mG placentas showed Cre-mediated recombinase activity as demonstrated by placental enhanced green fluorescent protein (EGFP) expression. Further genetic excision analysis of the placentas revealed consistent results showing the absence of excision of the tdTomato in all of the Cyp19-Cre;ROSAmT/mG placentas lacking EGFP expression. Moreover, among the EGFP-expressing placentas, there was wide variability in recombination efficiency, even in placentas from the same litter, leading to a mosaic pattern of EGFP expression in different zones and cell types of the placentas. In addition, we observed a significantly higher percentage of Cre recombination activity in placentas with maternal Cre inheritance. Our results show frequent mosaicism, inconsistent recombination activity, and parent-of-origin effects in placentas from Cyp19-Cre;ROSAmT/mG mice, suggesting that tail-biopsy genotype results may not necessarily indicate the excision of floxed genes in Cyp19-Cre positive placentas. Thus, placenta-specific mutagenesis studies using the Cyp19-Cre model require extensive characterization and careful interpretation of the placental phenotypes for each floxed allele.
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Affiliation(s)
- Prashanth Anamthathmakula
- Department of Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
- Department of Surgery, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Philemon D. Shallie
- Department of Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
- Department of Surgery, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Neha Nayak
- Department of Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Sabita Dhal
- Department of Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Jay L. Vivian
- Children’s Mercy Research Institute, Children’s Mercy, Kansas City, MO 64108, USA
| | - Gil Mor
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
| | - Michael J. Soares
- Institute for Reproductive and Developmental Sciences, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Center for Perinatal Research, Children’s Mercy Research Institute, Children’s Mercy, Kansas City, MO 64108, USA
| | - Nihar R. Nayak
- Department of Obstetrics and Gynecology, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
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14
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Iqbal K, Nixon B, Crnkovich B, Dominguez EM, Moreno-Irusta A, Scott RL, Vu HTH, Tuteja G, Vivian JL, Soares MJ. CONDITIONALLY MUTANT ANIMAL MODEL FOR INVESTIGATING THE INVASIVE TROPHOBLAST CELL LINEAGE. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.02.551740. [PMID: 37577576 PMCID: PMC10418272 DOI: 10.1101/2023.08.02.551740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
Placental development involves coordinated expansion and differentiation of trophoblast cell lineages possessing specialized functions. Among the differentiated trophoblast cell lineages are invasive trophoblast cells, which exit the placenta and invade into the uterus where they restructure the uterine parenchyma and facilitate remodeling of uterine spiral arteries. The rat exhibits deep intrauterine trophoblast cell invasion, a feature shared with human placentation, and is also amenable to gene manipulation using genome editing techniques. In this investigation, we generated a conditional rat model targeting the invasive trophoblast cell lineage. Prolactin family 7, subfamily b, member 1 ( Prl7b1 ) is uniquely and abundantly expressed in the rat invasive trophoblast cell lineage. Disruption of Prl7b1 did not adversely affect placental development. We demonstrated that the Prl7b1 locus could be effectively used to drive the expression of Cre recombinase in invasive trophoblast cells. Our rat model represents a new tool for investigating candidate genes contributing to the regulation of invasive trophoblast cells and their contributions to trophoblast-guided uterine spiral artery remodeling.
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15
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Bi S, Tu Z, Chen D, Zhang S. Histone modifications in embryo implantation and placentation: insights from mouse models. Front Endocrinol (Lausanne) 2023; 14:1229862. [PMID: 37600694 PMCID: PMC10436591 DOI: 10.3389/fendo.2023.1229862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 07/13/2023] [Indexed: 08/22/2023] Open
Abstract
Embryo implantation and placentation play pivotal roles in pregnancy by facilitating crucial maternal-fetal interactions. These dynamic processes involve significant alterations in gene expression profiles within the endometrium and trophoblast lineages. Epigenetics regulatory mechanisms, such as DNA methylation, histone modification, chromatin remodeling, and microRNA expression, act as regulatory switches to modulate gene activity, and have been implicated in establishing a successful pregnancy. Exploring the alterations in these epigenetic modifications can provide valuable insights for the development of therapeutic strategies targeting complications related to pregnancy. However, our current understanding of these mechanisms during key gestational stages remains incomplete. This review focuses on recent advancements in the study of histone modifications during embryo implantation and placentation, while also highlighting future research directions in this field.
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Affiliation(s)
- Shilei Bi
- Key Laboratory for Major Obstetric Diseases of Guangdong, Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China
- Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangzhou, China
| | - Zhaowei Tu
- Key Laboratory for Major Obstetric Diseases of Guangdong, Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China
- Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangzhou, China
| | - Dunjin Chen
- Key Laboratory for Major Obstetric Diseases of Guangdong, Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China
- Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangzhou, China
| | - Shuang Zhang
- Key Laboratory for Major Obstetric Diseases of Guangdong, Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China
- Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangzhou, China
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16
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Lee DY, Chun JN, Cho M, So I, Jeon JH. Emerging role of E2F8 in human cancer. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166745. [PMID: 37164180 DOI: 10.1016/j.bbadis.2023.166745] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 05/01/2023] [Accepted: 05/02/2023] [Indexed: 05/12/2023]
Abstract
E2F8 is a multifaceted transcription factor that plays a crucial role in mediating the hallmarks of cancer, including sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Aberrant E2F8 expression is associated with poor clinical outcomes in most human cancers. However, E2F8 also exhibits tumor-suppressing activity; thus, the role of E2F8 in cell-fate determination is unclear. In this review, we highlight the recent progress in understanding the role of E2F8 in human cancers, which will contribute to building a conceptual framework and broadening our knowledge pertaining to E2F8. This review provides insight into future challenges and perspectives regarding the translation of biological knowledge into therapeutic strategies for the treatment of cancer.
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Affiliation(s)
- Da Young Lee
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung Nyeo Chun
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea
| | - Minsoo Cho
- Independent researcher, Seoul, Republic of Korea
| | - Insuk So
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea
| | - Ju-Hong Jeon
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea.
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17
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Vu HT, Kaur H, Kies KR, Starks RR, Tuteja G. Identifying novel regulators of placental development using time-series transcriptome data. Life Sci Alliance 2023; 6:6/2/e202201788. [PMID: 36622342 PMCID: PMC9748866 DOI: 10.26508/lsa.202201788] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 12/15/2022] Open
Abstract
The placenta serves as a connection between the mother and the fetus during pregnancy, providing the fetus with oxygen, nutrients, and growth hormones. However, the regulatory mechanisms and dynamic gene interaction networks underlying early placental development are understudied. Here, we generated RNA-sequencing data from mouse fetal placenta at embryonic days 7.5, 8.5, and 9.5 to identify genes with timepoint-specific expression, then inferred gene interaction networks to analyze highly connected network modules. We determined that timepoint-specific gene network modules were associated with distinct developmental processes, and with similar expression profiles to specific human placental cell populations. From each module, we identified hub genes and their direct neighboring genes, which were predicted to govern placental functions. We confirmed that four novel candidate regulators identified through our analyses regulate cell migration in the HTR-8/SVneo cell line. Overall, we predicted several novel regulators of placental development expressed in specific placental cell types using network analysis of bulk RNA-sequencing data. Our findings and analysis approaches will be valuable for future studies investigating the transcriptional landscape of early development.
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Affiliation(s)
- Ha Th Vu
- Genetics, Development, and Cell Biology, Iowa State University, Ames, IA, USA.,Bioinformatics and Computational Biology, Iowa State University, Ames, IA, USA
| | - Haninder Kaur
- Genetics, Development, and Cell Biology, Iowa State University, Ames, IA, USA
| | - Kelby R Kies
- Genetics, Development, and Cell Biology, Iowa State University, Ames, IA, USA.,Bioinformatics and Computational Biology, Iowa State University, Ames, IA, USA
| | - Rebekah R Starks
- Genetics, Development, and Cell Biology, Iowa State University, Ames, IA, USA.,Bioinformatics and Computational Biology, Iowa State University, Ames, IA, USA
| | - Geetu Tuteja
- Genetics, Development, and Cell Biology, Iowa State University, Ames, IA, USA .,Bioinformatics and Computational Biology, Iowa State University, Ames, IA, USA
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18
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Li J, Wang L, Ding J, Cheng Y, Diao L, Li L, Zhang Y, Yin T. Multiomics Studies Investigating Recurrent Pregnancy Loss: An Effective Tool for Mechanism Exploration. Front Immunol 2022; 13:826198. [PMID: 35572542 PMCID: PMC9094436 DOI: 10.3389/fimmu.2022.826198] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/31/2022] [Indexed: 12/18/2022] Open
Abstract
Patients with recurrent pregnancy loss (RPL) account for approximately 1%-5% of women aiming to achieve childbirth. Although studies have shown that RPL is associated with failure of endometrial decidualization, placental dysfunction, and immune microenvironment disorder at the maternal-fetal interface, the exact pathogenesis remains unknown. With the development of high-throughput technology, more studies have focused on the genomics, transcriptomics, proteomics and metabolomics of RPL, and new gene mutations and new biomarkers of RPL have been discovered, providing an opportunity to explore the pathogenesis of RPL from different biological processes. Bioinformatics analyses of these differentially expressed genes, proteins and metabolites also reflect the biological pathways involved in RPL, laying a foundation for further research. In this review, we summarize the findings of omics studies investigating decidual tissue, villous tissue and blood from patients with RPL and identify some possible limitations of current studies.
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Affiliation(s)
- Jianan Li
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Linlin Wang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China.,Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
| | - Jinli Ding
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yanxiang Cheng
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lianghui Diao
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
| | - Longfei Li
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Shenzhen Zhongshan Urology Hospital, Shenzhen, China
| | - Yan Zhang
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Tailang Yin
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
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19
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Dong C, Fu S, Karvas RM, Chew B, Fischer LA, Xing X, Harrison JK, Popli P, Kommagani R, Wang T, Zhang B, Theunissen TW. A genome-wide CRISPR-Cas9 knockout screen identifies essential and growth-restricting genes in human trophoblast stem cells. Nat Commun 2022; 13:2548. [PMID: 35538076 PMCID: PMC9090837 DOI: 10.1038/s41467-022-30207-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 04/21/2022] [Indexed: 12/26/2022] Open
Abstract
The recent derivation of human trophoblast stem cells (hTSCs) provides a scalable in vitro model system of human placental development, but the molecular regulators of hTSC identity have not been systematically explored thus far. Here, we utilize a genome-wide CRISPR-Cas9 knockout screen to comprehensively identify essential and growth-restricting genes in hTSCs. By cross-referencing our data to those from similar genetic screens performed in other cell types, as well as gene expression data from early human embryos, we define hTSC-specific and -enriched regulators. These include both well-established and previously uncharacterized trophoblast regulators, such as ARID3A, GATA2, and TEAD1 (essential), and GCM1, PTPN14, and TET2 (growth-restricting). Integrated analysis of chromatin accessibility, gene expression, and genome-wide location data reveals that the transcription factor TEAD1 regulates the expression of many trophoblast regulators in hTSCs. In the absence of TEAD1, hTSCs fail to complete faithful differentiation into extravillous trophoblast (EVT) cells and instead show a bias towards syncytiotrophoblast (STB) differentiation, thus indicating that this transcription factor safeguards the bipotent lineage potential of hTSCs. Overall, our study provides a valuable resource for dissecting the molecular regulation of human placental development and diseases.
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Affiliation(s)
- Chen Dong
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Shuhua Fu
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Rowan M Karvas
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Brian Chew
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Laura A Fischer
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Xiaoyun Xing
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
- Department of Genetics, Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Jessica K Harrison
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
- Department of Genetics, Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Pooja Popli
- Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Ramakrishna Kommagani
- Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Ting Wang
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
- Department of Genetics, Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Bo Zhang
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
| | - Thorold W Theunissen
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
- Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
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20
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Rosenfeld CS. The placenta as a target of opioid drugs†. Biol Reprod 2022; 106:676-686. [PMID: 35024817 PMCID: PMC9040663 DOI: 10.1093/biolre/ioac003] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/20/2021] [Accepted: 01/15/2022] [Indexed: 01/14/2023] Open
Abstract
Opioid drugs are analgesics increasingly being prescribed to control pain associated with a wide range of causes. Usage of pregnant women has dramatically increased in the past decades. Neonates born to these women are at risk for neonatal abstinence syndrome (also referred to as neonatal opioid withdrawal syndrome). Negative birth outcomes linked with maternal opioid use disorder include compromised fetal growth, premature birth, reduced birthweight, and congenital defects. Such infants require lengthier hospital stays necessitating rising health care costs, and they are at greater risk for neurobehavioral and other diseases. Thus, it is essential to understand the genesis of such disorders. As the primary communication organ between mother and conceptus, the placenta itself is susceptible to opioid effects but may be key to understanding how these drugs affect long-term offspring health and potential avenue to prevent later diseases. In this review, we will consider the evidence that placental responses are regulated through an endogenous opioid system. However, maternal consumption of opioid drugs can also bind and act through opioid receptors express by trophoblast cells of the placenta. Thus, we will also discuss the current human and rodent studies that have examined the effects of opioids on the placenta. These drugs might affect placental hormones associated with maternal recognition of pregnancy, including placental lactogens and human chorionic gonadotropin in rodents and humans, respectively. A further understanding of how such drugs affect the placenta may open up new avenues for early diagnostic and remediation approaches.
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Affiliation(s)
- Cheryl S Rosenfeld
- Department of Biomedical Sciences, University of Missouri, Columbia, MO, USA
- MU Institute of Data Science and Informatics, University of Missouri, Columbia, MO, USA
- Genetics Area Program, University of Missouri, Columbia, MO, USA
- Thompson Center for Autism and Neurobehavioral Disorders, University of Missouri, Columbia, MO, USA
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21
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Mäkelä JA, Toppari J. Retinoblastoma-E2F Transcription Factor Interplay Is Essential for Testicular Development and Male Fertility. Front Endocrinol (Lausanne) 2022; 13:903684. [PMID: 35663332 PMCID: PMC9161260 DOI: 10.3389/fendo.2022.903684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/11/2022] [Indexed: 01/11/2023] Open
Abstract
The retinoblastoma (RB) protein family members (pRB, p107 and p130) are key regulators of cell cycle progression, but also play crucial roles in apoptosis, and stem cell self-renewal and differentiation. RB proteins exert their effects through binding to E2F transcription factors, which are essential developmental and physiological regulators of tissue and organ homeostasis. According to the canonical view, phosphorylation of RB results in release of E2Fs and induction of genes needed for progress of the cell cycle. However, there are eight members in the E2F transcription factor family with both activator (E2F1-3a) and repressor (E2F3b-E2F8) roles, highlighting the functional diversity of RB-E2F pathway. In this review article we summarize the data showing that RB-E2F interaction is a key cell-autonomous mechanism responsible for establishment and maintenance of lifelong male fertility. We also review the expression pattern of RB proteins and E2F transcription factors in the testis and male germ cells. The available evidence supports that RB and E2F family members are widely and dynamically expressed in the testis, and they are known to have versatile roles during spermatogenesis. Knowledge of the function and significance of RB-E2F interplay for testicular development and spermatogenesis comes primarily from gene knock-out (KO) studies. Several studies conducted in Sertoli cell-specific pRB-KO mice have demonstrated that pRB-mediated inhibition of E2F3 is essential for Sertoli cell functional maturation and cell cycle exit, highlighting that RB-E2F interaction in Sertoli cells is paramount to male fertility. Similarly, ablation of either pRB or E2F1 in the germline results in progressive testicular atrophy due to germline stem cell (GSC) depletion, emphasizing the importance of proper RB-E2F interplay for germline maintenance and lifelong sperm production. In summary, while balanced RB-E2F interplay is essential for cell-autonomous maintenance of GSCs and, the pRB-E2F3 system in Sertoli cells is critical for providing GSC niche thus laying the basis for spermatogenesis.
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Affiliation(s)
- Juho-Antti Mäkelä
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
| | - Jorma Toppari
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
- Department of Pediatrics, Turku University Hospital, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
- *Correspondence: Jorma Toppari,
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22
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Schierding W, Horsfield JA, O'Sullivan JM. Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways. J Med Genet 2021; 58:534-542. [PMID: 32917770 PMCID: PMC8327319 DOI: 10.1136/jmedgenet-2020-107095] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/08/2020] [Accepted: 06/20/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND The cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components can be sufficient to produce a disease phenotype. The implication that genes encoding the cohesin subunits or cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested. METHODS Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci (Mitotic: SMC1A, SMC3, STAG1, STAG2, RAD21/RAD21-AS; Meiotic: SMC1B, STAG3, REC8, RAD21L1), cohesin-ring support genes (NIPBL, MAU2, WAPL, PDS5A, PDS5B) and CTCF, including linking their expression to that of other genes. We searched the genome-wide association studies (GWAS) catalogue for SNPs mapped or attributed to cohesin genes by GWAS (GWAS-attributed) and the GTEx catalogue for SNPs mapped to cohesin genes by cis-regulatory variants in one or more of 44 tissues across the human body (expression quantitative trail locus-attributed). RESULTS Connections that centre on the cohesin ring subunits provide evidence of coordinated regulation that has little tolerance for perturbation. We used the CoDeS3D SNP-gene attribution methodology to identify transcriptional changes across a set of genes coregulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are coregulated with cohesin loci are themselves intolerant to loss-of-function. CONCLUSIONS The results highlight the importance of robust regulation of cohesin genes and implicate novel pathways that may be important in the human cohesinopathy disorders.
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Affiliation(s)
| | - Julia A Horsfield
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
| | - Justin M O'Sullivan
- Liggins Institute, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, Hampshire, UK
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23
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Ter Huurne M, Stunnenberg HG. G1-phase progression in pluripotent stem cells. Cell Mol Life Sci 2021; 78:4507-4519. [PMID: 33884444 PMCID: PMC8195903 DOI: 10.1007/s00018-021-03797-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/19/2021] [Accepted: 02/19/2021] [Indexed: 11/10/2022]
Abstract
During early embryonic development both the rapid increase in cell number and the expression of genes that control developmental decisions are tightly regulated. Accumulating evidence has indicated that these two seemingly independent processes are mechanistically intertwined. The picture that emerges from studies on the cell cycle of embryonic stem cells is one in which proteins that promote cell cycle progression prevent differentiation and vice versa. Here, we review which transcription factors and signalling pathways play a role in both maintenance of pluripotency as well as cell cycle progression. We will not only describe the mechanism behind their function but also discuss the role of these regulators in different states of mouse pluripotency. Finally, we elaborate on how canonical cell cycle regulators impact on the molecular networks that control the maintenance of pluripotency and lineage specification.
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Affiliation(s)
- Menno Ter Huurne
- Department of Molecular Biology, Faculty of Science, Radboud University, 6525GA, Nijmegen, The Netherlands
- Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Rd, Parkville, Melbourne, VIC, 3052, Australia
| | - Hendrik G Stunnenberg
- Department of Molecular Biology, Faculty of Science, Radboud University, 6525GA, Nijmegen, The Netherlands.
- Princess Maxima Centre for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands.
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24
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Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context. Cancers (Basel) 2021; 13:cancers13092033. [PMID: 33922435 PMCID: PMC8122802 DOI: 10.3390/cancers13092033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 11/24/2022] Open
Abstract
Simple Summary In virtually all human malignancies, the CDK-RB-E2F pathway is dysregulated resulting in the activation of the E2F transcriptional network. Rb and atypical E2Fs are the most important negative regulators of E2F-dependent transcription during tumorigenesis. However, it is unknown whether they cooporate or act independently in tumor development. Here we show that combined loss of RB and atypical E2Fs in mice enhances tumorigenesis in the liver, while in the pituitary gland, we observe inhibition of tumorigenesis. These findings suggest that the interaction between RB and atypical E2Fs in controlling tumorigenesis occurs in a tissue cell-type specific manner. Abstract E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanisms. The best-known is the Retinoblastoma protein (RB), which is mutated in many cancers. Atypical E2Fs (E2F7 and −8) can repress E2F-target gene expression independently of RB and are rarely mutated in cancer. Therefore, they may act as emergency brakes in RB-mutated cells to suppress tumor growth. Currently, it is unknown if and how RB and atypical E2Fs functionally interact in vivo. Here, we demonstrate that mice with liver-specific combinatorial deletion of Rb and E2f7/8 have reduced life-spans compared to E2f7/8 or Rb deletion alone. This was associated with increased proliferation and enhanced malignant progression of liver tumors. Hence, atypical repressor E2Fs and RB cooperatively act as tumor suppressors in hepatocytes. In contrast, loss of either E2f7 or E2f8 largely prevented the formation of pituitary tumors in Rb+/− mice. To test whether atypical E2Fs can also function as oncogenes independent of RB loss, we induced long-term overexpression of E2f7 or E2f8 in mice. E2F7 and −8 overexpression increased the incidence of tumors in the lungs, but not in other tissues. Collectively, these data show that atypical E2Fs can promote but also inhibit tumorigenesis depending on tissue type and RB status. We propose that the complex interactions between atypical E2Fs and RB on maintenance of genetic stability underlie this context-dependency.
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25
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Luinenburg DG, Dinitzen AB, Flohr Svendsen A, Cengiz R, Ausema A, Weersing E, Bystrykh L, de Haan G. Persistent expression of microRNA-125a targets is required to induce murine hematopoietic stem cell repopulating activity. Exp Hematol 2021; 94:47-59.e5. [PMID: 33333212 DOI: 10.1016/j.exphem.2020.12.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/10/2020] [Accepted: 12/11/2020] [Indexed: 01/17/2023]
Abstract
MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression posttranscriptionally by binding to the 3' untranslated regions of their target mRNAs. The evolutionarily conserved microRNA-125a (miR-125a) is highly expressed in both murine and human hematopoietic stem cells (HSCs), and previous studies have found that miR-125 strongly enhances self-renewal of HSCs and progenitors. In this study we explored whether temporary overexpression of miR-125a would be sufficient to permanently increase HSC self-renewal or, rather, whether persistent overexpression of miR-125a is required. We used three complementary in vivo approaches to reversibly enforce expression of miR-125a in murine HSCs. Additionally, we interrogated the underlying molecular mechanisms responsible for the functional changes that occur in HSCs on overexpression of miR-125a. Our data indicate that continuous expression of miR-125a is required to enhance HSC activity. Our molecular analysis confirms changes in pathways that explain the characteristics of miR-125a overexpressing HSCs. Moreover, it provides several novel putative miR-125a targets, but also highlights the complex molecular changes that collectively lead to enhanced HSC function.
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Affiliation(s)
- Daniëlle G Luinenburg
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Alexander Bak Dinitzen
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Arthur Flohr Svendsen
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Roza Cengiz
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Albertina Ausema
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ellen Weersing
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Leonid Bystrykh
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gerald de Haan
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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26
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Laisk T, Soares ALG, Ferreira T, Painter JN, Censin JC, Laber S, Bacelis J, Chen CY, Lepamets M, Lin K, Liu S, Millwood IY, Ramu A, Southcombe J, Andersen MS, Yang L, Becker CM, Børglum AD, Gordon SD, Bybjerg-Grauholm J, Helgeland Ø, Hougaard DM, Jin X, Johansson S, Juodakis J, Kartsonaki C, Kukushkina V, Lind PA, Metspalu A, Montgomery GW, Morris AP, Mors O, Mortensen PB, Njølstad PR, Nordentoft M, Nyholt DR, Lippincott M, Seminara S, Salumets A, Snieder H, Zondervan K, Werge T, Chen Z, Conrad DF, Jacobsson B, Li L, Martin NG, Neale BM, Nielsen R, Walters RG, Granne I, Medland SE, Mägi R, Lawlor DA, Lindgren CM. The genetic architecture of sporadic and multiple consecutive miscarriage. Nat Commun 2020; 11:5980. [PMID: 33239672 PMCID: PMC7689465 DOI: 10.1038/s41467-020-19742-5] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/23/2020] [Indexed: 12/17/2022] Open
Abstract
Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10-8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10-8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10-9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10-8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
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Affiliation(s)
- Triin Laisk
- Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
- Competence Centre on Health Technologies, Tartu, Estonia.
| | - Ana Luiza G Soares
- MRC Integrated Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Teresa Ferreira
- Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford University, Oxford, UK
| | - Jodie N Painter
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Jenny C Censin
- Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford University, Oxford, UK
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Samantha Laber
- Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford University, Oxford, UK
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Jonas Bacelis
- Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra, Gothenburg, Sweden
| | - Chia-Yen Chen
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
- Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Maarja Lepamets
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
- Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Kuang Lin
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Siyang Liu
- BGI-Shenzhen, Shenzhen, 518083, Guangdong, China
- Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Iona Y Millwood
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK
| | - Avinash Ramu
- Department of Genetics, Washington University in St. Louis, Saint Louis, MO, USA
| | - Jennifer Southcombe
- Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK
| | | | - Ling Yang
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK
| | - Christian M Becker
- Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK
| | - Anders D Børglum
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
- Department of Biomedicine and Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark
- Center for Genomics and Personalized Medicine, Aarhus University and University Hospital, Aarhus, Denmark
| | - Scott D Gordon
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Jonas Bybjerg-Grauholm
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
- Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | - Øyvind Helgeland
- Department of Genetics and Bioinformatics, Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway
- KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway
| | - David M Hougaard
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
- Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | - Xin Jin
- BGI-Shenzhen, Shenzhen, 518083, Guangdong, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Stefan Johansson
- KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway
- Department of Medical Genetics, Haukeland University Hospital, N-5021, Bergen, Norway
| | - Julius Juodakis
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Christiana Kartsonaki
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK
| | - Viktorija Kukushkina
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
- Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Penelope A Lind
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Andres Metspalu
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | | | - Andrew P Morris
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
- Department of Biostatistics, University of Liverpool, Liverpool, UK
| | - Ole Mors
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
- Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark
| | - Preben B Mortensen
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
- National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
| | - Pål R Njølstad
- KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway
- Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
| | - Merete Nordentoft
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
- Copenhagen University Hospital, Mental Health Center Copenhagen, Mental Health Services in the Capital Region of Denmark, Copenhagen, Denmark
| | - Dale R Nyholt
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Margaret Lippincott
- Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Stephanie Seminara
- Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Andres Salumets
- Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
- Competence Centre on Health Technologies, Tartu, Estonia
- Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Harold Snieder
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Krina Zondervan
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
- Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK
| | - Thomas Werge
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
- Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Zhengming Chen
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Donald F Conrad
- Department of Genetics, Washington University in St. Louis, Saint Louis, MO, USA
| | - Bo Jacobsson
- Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra, Gothenburg, Sweden
- Department of Genetics and Bioinformatics, Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway
| | - Liming Li
- Department of Epidemiology & Biostatistics, Peking University Health Science Centre, Peking University, Beijing, China
| | | | - Benjamin M Neale
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
- Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Rasmus Nielsen
- Department of Integrative Biology, University of California Berkeley, Berkeley, CA, USA
- Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark
| | - Robin G Walters
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK
| | - Ingrid Granne
- Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK
| | - Sarah E Medland
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Reedik Mägi
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Deborah A Lawlor
- MRC Integrated Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Bristol National Institute of Health Research Biomedical Research Centre, Bristol, UK
| | - Cecilia M Lindgren
- Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford University, Oxford, UK.
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
- Program in Medical and Population Genetics, Broad Institute, Boston, MA, USA.
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27
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Yang Y, Deng X, Li Q, Wang F, Miao L, Jiang Q. Emerging roles of long noncoding RNAs in cholangiocarcinoma: Advances and challenges. Cancer Commun (Lond) 2020; 40:655-680. [PMID: 33142045 PMCID: PMC7743012 DOI: 10.1002/cac2.12109] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 10/10/2020] [Accepted: 10/21/2020] [Indexed: 12/19/2022] Open
Abstract
Cholangiocarcinoma (CCA), a cancer with a relatively low incidence rate, is usually associated with poor prognosis. Current modalities for the diagnosis and treatment of CCA patients are still far from satisfactory. In recent years, numerous long noncoding RNAs (lncRNAs) have been identified as crucial players in the development of various cancers, including CCA. Abnormally expressed lncRNAs in CCA, regulated by some upstream molecules, significantly influence the biological behavior of tumor cells and are involved in tumor development through various mechanisms, including interactions with functional proteins, participation in competing for endogenous RNA (ceRNA) regulatory networks, activation of cancer‐related signaling pathways and epigenetic modification of gene expression. Furthermore, several lncRNAs are closely associated with the clinicopathological features of CCA patients, and are promising biomarkers for diagnosing and prognostication of CCA. Some of these lncRNAs play an important role in chemotherapy drug resistance. In addition, lncRNAs have also been shown to be involved in the inflammation microenvironment of CCA and malignant outcome of CCA risk factors, such as cholestatic liver diseases. In view of the difficulty of diagnosing CCA, more attention should be paid to detectable lncRNAs in the serum or bile. This review summarizes the recent knowledge on lncRNAs in CCA and provides a new outlook on the molecular mechanisms of CCA development from the perspective of lncRNAs. Moreover, we also discussed the limitations of the current studies and differential expression of lncRNAs in different types of CCA.
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Affiliation(s)
- Yang Yang
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, P. R. China.,Nanjing Medical University, Nanjing, Jiangsu, 210000, P. R. China
| | - Xueting Deng
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, P. R. China.,Nanjing Medical University, Nanjing, Jiangsu, 210000, P. R. China
| | - Quanpeng Li
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, P. R. China.,Nanjing Medical University, Nanjing, Jiangsu, 210000, P. R. China
| | - Fei Wang
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, P. R. China.,Nanjing Medical University, Nanjing, Jiangsu, 210000, P. R. China
| | - Lin Miao
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210000, P. R. China.,Nanjing Medical University, Nanjing, Jiangsu, 210000, P. R. China
| | - Qi Jiang
- Department of Gastroenterology, Dongtai People's Hospital, Yancheng, Jiangsu, 224000, P. R. China
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Y-Box Binding Protein 1 Expression in Trophoblast Cells Promotes Fetal and Placental Development. Cells 2020; 9:cells9091942. [PMID: 32842598 PMCID: PMC7563187 DOI: 10.3390/cells9091942] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/20/2020] [Accepted: 08/21/2020] [Indexed: 12/14/2022] Open
Abstract
Y-box binding protein 1 (YB-1) is pivotal for the regulation of cancerogenesis and inflammation. However, its involvement in pregnancy processes such as fetal and placental development remains to be elucidated. We studied Ybx1 (YB-1)+/− heterozygous intercrossings and compared them to YB-1+/+ wild-type (WT) combinations. Additionally, we generated trophoblast-specific YB-1-deficient mice by pairing FVB Cyp19-Cre females to YB-1fl/fl males. YB-1fl/fl-paired FVB WT females served as controls. Serial in vivo ultrasound measurements were performed to assess fetal and placental parameters. After sacrificing the females, implantation and abortion rates were recorded, spiral artery (SA) remodeling was analyzed and fetal and placental weights were determined. Compared to YB-1+/+ counterparts, YB-1+/− females showed reduced implantation areas at gestation day (GD)10, insufficiently remodeled SAs at GD12, increased placental diameter/thickness ratios at GD14 and reduced placental and fetal weights at GD14. Compared to WT, Cyp19-Cre females with YB-1-deficient placentas showed reduced implantation areas at GD8, 10 and 12; decreased placental areas and diameters at GD10 and 12; diminished placental thicknesses at GD12; as well as reduced placental weights at GD12 and 14. In conclusion, our data suggest haploinsufficiency of YB-1 resulting in disturbed fetal and placental development. Moreover, we provide the first evidence for the relevance of trophoblast-specific YB-1 for placentation.
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29
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E2F8 Induces Cell Proliferation and Invasion through the Epithelial-Mesenchymal Transition and Notch Signaling Pathways in Ovarian Cancer. Int J Mol Sci 2020; 21:ijms21165813. [PMID: 32823614 PMCID: PMC7460858 DOI: 10.3390/ijms21165813] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/02/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open
Abstract
Background: Despite the recent research implicating E2F8 (E2F Transcription Factor 8) in cancer, the role of E2F8 in the progression of ovarian cancer has remained unclear. Hence, we explored the bio-functional effects of E2F8 knockdown on ovarian cancer cell lines in vitro and in vivo. Methods: The expression of E2F8 was compared between ovarian cancer and noncancer tissues, and its association with the progression-free survival of ovarian cancer patients was analyzed. To demonstrate the function of E2F8 in cell proliferation, migration, and invasion, we employed RNA interference to suppress E2F8 expression in ovarian cancer cell lines. Finally, the effect of E2F8 knockdown was investigated in a xenograft mouse model of ovarian cancer. Results: Ovarian cancer tissue exhibited significantly higher E2F8 expression compared to that of normal ovarian tissue. Clinical data showed that E2F8 was a significant predictor of progression-free survival. Moreover, the prognosis of the ovarian cancer patients with high E2F8 expression was poorer than that of the patients with low E2F8 expression. In vitro experiments using E2F8-knockdown ovarian cancer cell lines demonstrated that E2F8 knockdown inhibited cell proliferation, migration, and tumor invasion. Additionally, E2F8 was a potent inducer and modulator of the expression of epithelial–mesenchymal transition and Notch signaling pathway-related markers. We confirmed the function of E2F8 in vivo, signifying that E2F8 knockdown was significantly correlated with reduced tumor size and weight. Conclusions: Our findings indicate that E2F8 is highly correlated with ovarian cancer progression. Hence, E2F8 can be utilized as a prognostic marker and therapeutic target against ovarian malignancy.
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Abstract
Polyploidy (or whole-genome duplication) is the condition of having more than two basic sets of chromosomes. Polyploidization is well tolerated in many species and can lead to specific biological functions. In mammals, programmed polyploidization takes place during development in certain tissues, such as the heart and placenta, and is considered a feature of differentiation. However, unscheduled polyploidization can cause genomic instability and has been observed in pathological conditions, such as cancer. Polyploidy of the liver parenchyma was first described more than 100 years ago. The liver is one of the few mammalian organs that display changes in polyploidy during homeostasis, regeneration and in response to damage. In the human liver, approximately 30% of hepatocytes are polyploid. The polyploidy of hepatocytes results from both nuclear polyploidy (an increase in the amount of DNA per nucleus) and cellular polyploidy (an increase in the number of nuclei per cell). In this Review, we discuss the regulation of polyploidy in liver development and pathophysiology. We also provide an overview of current knowledge about the mechanisms of hepatocyte polyploidization, its biological importance and the fate of polyploid hepatocytes during liver tumorigenesis.
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31
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Wang H, Wang L, Tang L, Luo J, Ji H, Zhang W, Zhou J, Li Q, Miao L. Long noncoding RNA SNHG6 promotes proliferation and angiogenesis of cholangiocarcinoma cells through sponging miR-101-3p and activation of E2F8. J Cancer 2020; 11:3002-3012. [PMID: 32226515 PMCID: PMC7086249 DOI: 10.7150/jca.40592] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 02/02/2020] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma (CCA) development is an extremely complex process with alterations occurring in numerous genes. SNHG6, a validated lncRNA, has been reported to regulate the expression of multiple tumor-related genes in hepatocellular carcinoma, colorectal cancer and breast cancer. Here, we elucidated the function and possible molecular mechanisms of SNHG6 in human CCA cells. Our results proved that the expression SNHG6 was upregulated in CCA tissues and cell lines. Ectopic expression of SNHG6 promoted cell proliferation, cell cycle progression, migration, and angiogenesis in CCA cells, whereas knockdown of SNHG6 repressed these cellular processes. Further mechanistic studies revealed that SNHG6 could compete with the transcription factor E2F8 to bind with miR-101-3p, thus affecting E2F8 expression. Taken together, these results provided a comprehensive analysis of the role of SNHG6 in CCA cells and offered important clues to understand the key roles of competing endogenous RNA (ceRNA) mechanisms in human cholangiocarcinoma.
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Affiliation(s)
- Huishan Wang
- Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, Jiangsu Province, China
| | - Li Wang
- Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, Jiangsu Province, China
| | - Lingyu Tang
- Taizhou hospital of traditional Chinese medicine, 86 Jichuandong Road, Hailing District, Taizhou 225300, Jiangsu Province, China
| | - Jing Luo
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Ji
- Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, Jiangsu Province, China
| | - Wen Zhang
- Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, Jiangsu Province, China
| | - Jian Zhou
- Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, Jiangsu Province, China
| | - Quanpeng Li
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiangjiayuan, Nanjing 210011, Jiangsu Province, China
| | - Lin Miao
- Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, Jiangsu Province, China
- Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiangjiayuan, Nanjing 210011, Jiangsu Province, China
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32
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Wu B, Li L, Li B, Gao J, Chen Y, Wei M, Yang Z, Zhang B, Li S, Li K, Wang C, Surani MA, Li X, Tang F, Bao S. Activin A and BMP4 Signaling Expands Potency of Mouse Embryonic Stem Cells in Serum-Free Media. Stem Cell Reports 2020; 14:241-255. [PMID: 32032551 PMCID: PMC7013251 DOI: 10.1016/j.stemcr.2020.01.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 01/07/2020] [Accepted: 01/08/2020] [Indexed: 02/06/2023] Open
Abstract
Inhibitors of Mek1/2 and Gsk3β, known as 2i, and, together with leukemia inhibitory factor, enhance the derivation of embryonic stem cells (ESCs) and promote ground-state pluripotency (2i/L-ESCs). However, recent reports show that prolonged Mek1/2 suppression impairs developmental potential of ESCs, and is rescued by serum (S/L-ESCs). Here, we show that culturing ESCs in Activin A and BMP4, and in the absence of MEK1/2 inhibitor (ABC/L medium), establishes advanced stem cells derived from ESCs (esASCs). We demonstrate that esASCs contributed to germline lineages, full-term chimeras and generated esASC-derived mice by tetraploid complementation. We show that, in contrast to 2i/L-ESCs, esASCs display distinct molecular signatures and a stable hypermethylated epigenome, which is reversible and similar to serum-cultured ESCs. Importantly, we also derived novel ASCs (blASCs) from blastocysts in ABC/L medium. Our results provide insights into the derivation of novel ESCs with DNA hypermethylation from blastocysts in chemically defined medium.
Activin A and BMP4 expand potency of mouse ESCs ASCs are hypermethylated and with stable genomic imprints ASCs developmentally closed to E4.5–E6.5 in vivo epiblast Hypermethylated ASCs directly derived from blastocyst by ABC/L medium
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Affiliation(s)
- Baojiang Wu
- The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010070, China; Research Center for Animal Genetic Resources of Mongolia Plateau, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China; Inner Mongolia Saikexing Institute of Breeding and Reproductive Biotechnology in Domestic Animal, Huhhot 011517, China
| | - Lin Li
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Beijing Advanced Innovation Center for Genomics and Biomedical Pioneering Innovation Center, College of Life Sciences, Peking University, Beijing 100871, China
| | - Bojiang Li
- College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China
| | - Junpeng Gao
- Beijing Advanced Innovation Center for Genomics and Biomedical Pioneering Innovation Center, College of Life Sciences, Peking University, Beijing 100871, China
| | - Yanglin Chen
- The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010070, China; Research Center for Animal Genetic Resources of Mongolia Plateau, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Mengyi Wei
- The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010070, China; Research Center for Animal Genetic Resources of Mongolia Plateau, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Zhiqing Yang
- The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010070, China; Research Center for Animal Genetic Resources of Mongolia Plateau, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Baojing Zhang
- The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010070, China; Research Center for Animal Genetic Resources of Mongolia Plateau, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Shudong Li
- Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
| | - Kexin Li
- The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010070, China
| | - Changshan Wang
- The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010070, China
| | - M Azim Surani
- Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK
| | - Xihe Li
- The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010070, China; Research Center for Animal Genetic Resources of Mongolia Plateau, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China; Inner Mongolia Saikexing Institute of Breeding and Reproductive Biotechnology in Domestic Animal, Huhhot 011517, China
| | - Fuchou Tang
- Beijing Advanced Innovation Center for Genomics and Biomedical Pioneering Innovation Center, College of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China.
| | - Siqin Bao
- The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010070, China; Research Center for Animal Genetic Resources of Mongolia Plateau, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China.
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Wasserman D, Nachum S, Cohen M, Enrico TP, Noach-Hirsh M, Parasol J, Zomer-Polak S, Auerbach N, Sheinberger-Chorni E, Nevenzal H, Levi-Dadon N, Wang X, Lahmi R, Michaely E, Gerber D, Emanuele MJ, Tzur A. Cell cycle oscillators underlying orderly proteolysis of E2F8. Mol Biol Cell 2020; 31:725-740. [PMID: 31995441 PMCID: PMC7185961 DOI: 10.1091/mbc.e19-12-0725] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
E2F8 is a transcriptional repressor that antagonizes E2F1 at the crossroads of the cell cycle, apoptosis, and cancer. Previously, we discovered that E2F8 is a direct target of the APC/C ubiquitin ligase. Nevertheless, it remains unknown how E2F8 is dynamically controlled throughout the entirety of the cell cycle. Here, using newly developed human cell-free systems that recapitulate distinct inter-mitotic and G1 phases and a continuous transition from prometaphase to G1, we reveal an interlocking dephosphorylation switch coordinating E2F8 degradation with mitotic exit and the activation of APC/CCdh1. Further, we uncover differential proteolysis rates for E2F8 at different points within G1 phase, accounting for its accumulation in late G1 while APC/CCdh1 is still active. Finally, we demonstrate that the F-box protein Cyclin F regulates E2F8 in G2-phase. Altogether, our data define E2F8 regulation throughout the cell cycle, illuminating an extensive coordination between phosphorylation, ubiquitination and transcription in mammalian cell cycle.
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Affiliation(s)
- Danit Wasserman
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Sapir Nachum
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Meital Cohen
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Taylor P Enrico
- Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Meirav Noach-Hirsh
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Jasmin Parasol
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Sarit Zomer-Polak
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Naomi Auerbach
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Evelin Sheinberger-Chorni
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Hadas Nevenzal
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Nofar Levi-Dadon
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Xianxi Wang
- Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Roxane Lahmi
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Efrat Michaely
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Doron Gerber
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
| | - Michael J Emanuele
- Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Amit Tzur
- Faculty of Life Sciences and Institute of Nanotechnology and Advanced Materials, Bar-llan University, Ramat-Gan 5290002, Israel
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Soares MJ, Varberg KM, Iqbal K. Hemochorial placentation: development, function, and adaptations. Biol Reprod 2019; 99:196-211. [PMID: 29481584 DOI: 10.1093/biolre/ioy049] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 02/21/2018] [Indexed: 11/12/2022] Open
Abstract
Placentation is a reproductive adaptation that permits fetal growth and development within the protected confines of the female reproductive tract. Through this important role, the placenta also determines postnatal health and susceptibility to disease. The hemochorial placenta is a prominent feature in primate and rodent development. This manuscript provides an overview of the basics of hemochorial placental development and function, provides perspectives on major discoveries that have shaped placental research, and thoughts on strategies for future investigation.
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Affiliation(s)
- Michael J Soares
- Institute for Reproduction and Perinatal Research and the Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.,Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kansas, USA and the Center for Perinatal Research, Children΄s Research Institute, Children΄s Mercy, Kansas City, Missouri, USA
| | - Kaela M Varberg
- Institute for Reproduction and Perinatal Research and the Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Khursheed Iqbal
- Institute for Reproduction and Perinatal Research and the Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
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35
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Outhwaite JE, Patel J, Simmons DG. Secondary Placental Defects in Cxadr Mutant Mice. Front Physiol 2019; 10:622. [PMID: 31338035 PMCID: PMC6628872 DOI: 10.3389/fphys.2019.00622] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 05/02/2019] [Indexed: 12/20/2022] Open
Abstract
The Coxsackie virus and adenovirus receptor (CXADR) is an adhesion molecule known for its role in virus-cell interactions, epithelial integrity, and organogenesis. Loss of Cxadr causes numerous embryonic defects in mice, notably abnormal development of the cardiovascular system, and embryonic lethality. While CXADR expression has been reported in the placenta, the precise cellular localization and function within this tissue are unknown. Since impairments in placental development and function can cause secondary cardiovascular abnormalities, a phenomenon referred to as the placenta-heart axis, it is possible placental phenotypes in Cxadr mutant embryos may underlie the reported cardiovascular defects and embryonic lethality. In the current study, we determine the cellular localization of placental Cxadr expression and whether there are placental abnormalities in the absence of Cxadr. In the placenta, CXADR is expressed specifically by trophoblast labyrinth progenitors as well as cells of the visceral yolk sac (YS). In the absence of Cxadr, we observed altered expression of angiogenic factors coupled with poor expansion of trophoblast and fetal endothelial cell subpopulations, plus diminished placental transport. Unexpectedly, preserving endogenous trophoblast Cxadr expression revealed the placental defects to be secondary to primary embryonic and/or YS phenotypes. Moreover, further tissue-restricted deletions of Cxadr suggest that the secondary placental defects are likely influenced by embryonic lineages such as the fetal endothelium or those within the extraembryonic YS vascular plexus.
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Affiliation(s)
- Jennifer E Outhwaite
- Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
| | - Jatin Patel
- Translational Research Institute, UQ Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - David G Simmons
- Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
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36
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Li X, Ma X, Tian F, Wu F, Zhang J, Zeng W, Lin Y, Zhang Y. Downregulation of
CCNA2
disturbs trophoblast migration, proliferation, and apoptosis during the pathogenesis of recurrent miscarriage. Am J Reprod Immunol 2019; 82:e13144. [PMID: 31087423 DOI: 10.1111/aji.13144] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 04/10/2019] [Accepted: 04/25/2019] [Indexed: 12/16/2022] Open
Affiliation(s)
- Xiao Li
- Shanghai Key Laboratory of Embryo Original Diseases The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Xiao‐Ling Ma
- Shanghai Key Laboratory of Embryo Original Diseases The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Fu‐Ju Tian
- Shanghai Key Laboratory of Embryo Original Diseases The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Fan Wu
- Shanghai Key Laboratory of Embryo Original Diseases The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Jing Zhang
- Shanghai Key Laboratory of Embryo Original Diseases The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Wei‐Hong Zeng
- Shanghai Key Laboratory of Embryo Original Diseases The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Yi Lin
- Shanghai Key Laboratory of Embryo Original Diseases The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Yan Zhang
- Department of Obstetrics and Gynecology Renmin Hospital of Wuhan University Wuhan China
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Chang H, Song J, Wu J, Zhang Y. E2F transcription factor 8 promotes cell proliferation via CCND1/p21 in esophageal squamous cell carcinoma. Onco Targets Ther 2018; 11:8165-8173. [PMID: 30532557 PMCID: PMC6241692 DOI: 10.2147/ott.s180938] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Purpose E2F transcription factor 8 (E2F8) is a novel member of the E2F family, but its function in esophageal squamous cell carcinoma (ESCC) remains unclear. This study aimed to research the function of E2F8 in ESCC. Materials and methods We used quantitative real-time PCR and Western blot analyses to detect the expression pattern of E2F8 in ESCC. The effects of E2F8 on proliferation were investigated by Cell Counting Kit-8, 5-ethynyl-2′-deoxyuridine, and colony formation assays. We also confirmed the function of E2F8 in vivo. Results E2F8 expression was upregulated in ESCC, and promoted cell proliferation and influenced the expression of CCND1/p21. Downregulation of E2F8 expression inhibited cell proliferation in vivo. Conclusion E2F8 was identified as a new potential oncogene in ESCC.
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Affiliation(s)
- Huiwen Chang
- Department of Cardiothoracic Surgery, Yancheng Third People's Hospital, The Affiliated Yancheng Hospital of Southeast University, Yancheng, Jiangsu 224001, PR China,
| | - Jianxiang Song
- Department of Cardiothoracic Surgery, Yancheng Third People's Hospital, The Affiliated Yancheng Hospital of Southeast University, Yancheng, Jiangsu 224001, PR China,
| | - Jixiang Wu
- Department of Cardiothoracic Surgery, Yancheng Third People's Hospital, The Affiliated Yancheng Hospital of Southeast University, Yancheng, Jiangsu 224001, PR China,
| | - Yajun Zhang
- Department of Cardiothoracic Surgery, Yancheng Third People's Hospital, The Affiliated Yancheng Hospital of Southeast University, Yancheng, Jiangsu 224001, PR China,
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38
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Mizuno M, Miki R, Moriyama Y, Ushida T, Imai K, Niimi K, Nakano T, Tsuda H, Sumigama S, Yamamoto E, Senga T, Iwase A, Kikkawa F, Kotani T. The role of E2F8 in the human placenta. Mol Med Rep 2018; 19:293-301. [PMID: 30387815 PMCID: PMC6297733 DOI: 10.3892/mmr.2018.9617] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 09/24/2018] [Indexed: 12/18/2022] Open
Abstract
Recent studies have reported that E2F transcription factor (E2F) 8, an atypical E2F transcription factor, serves a critical role in promoting the growth and development of the murine placenta. However, the function of E2F8 in the human placenta remains unknown. Invasion of extravillous trophoblasts (EVTs) into the maternal decidua is known to be important for the development of the human placenta. To investigate the role of E2F8 in human placental development, E2F8 localisation was examined in the human placenta and E2F8 mRNA expression was detected in primary cultured EVTs. The human EVT cell line, HTR‑8/SVneo, was divided into two groups and treated separately, one with retrovirus expressing short hairpin (sh)‑RNA against E2F8 (shE2F8 cells) and the other with non‑target control shRNA (shControl cells). The cell functions, including cell cycle, proliferation, invasion and adhesion, were compared between the shE2F8 and shControl cells. A histological examination revealed that E2F8 was localised in the decidua cells, EVTs, and cytotrophoblasts in the placenta. E2F8 mRNA was confirmed to be expressed in cultured primary EVTs. No significant difference was observed in the cell cycle, proliferation or adhesion between the shE2F8 and shControl cells. The invasive ability was ~2‑fold higher in the shE2F8 cells when compared with the shControl cells (P<0.01). Production of matrix metalloproteinase‑1 was significantly increased in the shE2F8 cells when compared with the shControl cells (P<0.05). Taken together, E2F8 is present in the EVTs of the human placenta, but, unlike murine placenta, it may suppress the invasiveness of EVTs. E2F8 was also present in cytotrophoblasts in cell columns, which have no invasive ability and differentiate into EVTs. In conclusion, E2F8 also exists in the human placenta, and its function may be different from that in the murine placenta, although further investigation is required.
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Affiliation(s)
- Masako Mizuno
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
| | - Rika Miki
- Laboratory of Bell Research Center‑Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
| | - Yoshinori Moriyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
| | - Takafumi Ushida
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
| | - Kenji Imai
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
| | - Kaoru Niimi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
| | - Tomoko Nakano
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
| | - Hiroyuki Tsuda
- Department of Obstetrics and Gynecology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Aichi 453‑8511, Japan
| | - Seiji Sumigama
- Office of International Affairs, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
| | - Eiko Yamamoto
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
| | - Takeshi Senga
- Department of Internal Medicine, Yahagigawa Hospital, Anjo, Aichi 444‑1164, Japan
| | - Akira Iwase
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
| | - Fumitaka Kikkawa
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
| | - Tomomi Kotani
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
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39
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Read JE, Cabrera-Sharp V, Offord V, Mirczuk SM, Allen SP, Fowkes RC, de Mestre AM. Dynamic changes in gene expression and signalling during trophoblast development in the horse. Reproduction 2018; 156:313-330. [PMID: 30306765 PMCID: PMC6170800 DOI: 10.1530/rep-18-0270] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 07/04/2018] [Accepted: 07/10/2018] [Indexed: 12/20/2022]
Abstract
Equine chorionic girdle trophoblast cells play important endocrine and immune functions critical in supporting pregnancy. Very little is known about the genes and pathways that regulate chorionic girdle trophoblast development. Our aim was to identify genes and signalling pathways active in vivo in equine chorionic girdle trophoblast within a critical 7-days window. We exploited the late implantation of the equine conceptus to obtain trophoblast tissue. An Agilent equine 44K microarray was performed using RNA extracted from chorionic girdle and chorion (control) from equine pregnancy days 27, 30, 31 and 34 (n = 5), corresponding to the initiation of chorionic girdle trophoblast proliferation, differentiation and migration. Data were analysed using R packages limma and maSigPro, Ingenuity Pathway Analysis and DAVID and verified using qRT-PCR, promoter analysis, western blotting and migration assays. Microarray analysis showed gene expression (absolute log FC >2, FDR-adjusted P < 0.05) was rapidly and specifically induced in the chorionic girdle between days 27 and 34 (compared to day 27, day 30 = 116, day 31 = 317, day 34 = 781 genes). Pathway analysis identified 35 pathways modulated during chorionic girdle development (e.g. FGF, integrin, Rho GTPases, MAPK) including pathways that have limited description in mammalian trophoblast (e.g. IL-9, CD40 and CD28 signalling). Rho A and ERK/MAPK activity was confirmed as was a role for transcription factor ELF5 in regulation of the CGB promoter. The purity and accessibility of chorionic girdle trophoblast proved to be a powerful resource to identify candidate genes and pathways involved in early equine placental development.
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Affiliation(s)
- Jordan E Read
- Department of Comparative Biomedical SciencesThe Royal Veterinary College, Hertfordshire, UK
| | - Victoria Cabrera-Sharp
- Department of Comparative Biomedical SciencesThe Royal Veterinary College, Hertfordshire, UK
| | - Victoria Offord
- Research Support OfficeThe Royal Veterinary College, London, UK
| | - Samantha M Mirczuk
- Department of Comparative Biomedical SciencesThe Royal Veterinary College, Hertfordshire, UK
| | - Steve P Allen
- Department of Comparative Biomedical SciencesThe Royal Veterinary College, Hertfordshire, UK
| | - Robert C Fowkes
- Department of Comparative Biomedical SciencesThe Royal Veterinary College, Hertfordshire, UK
| | - Amanda M de Mestre
- Department of Comparative Biomedical SciencesThe Royal Veterinary College, Hertfordshire, UK
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40
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Okano-Uchida T, Kent LN, Ouseph MM, McCarty B, Frank JJ, Kladney R, Cuitino MC, Thompson JC, Coppola V, Asano M, Leone G. Endoreduplication of the mouse genome in the absence of ORC1. Genes Dev 2018; 32:978-990. [PMID: 29967292 PMCID: PMC6075035 DOI: 10.1101/gad.311910.118] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 05/09/2018] [Indexed: 01/24/2023]
Abstract
In this study, Okano-Uchida et al. describe the physiological role of ORC1 in mice by generating knock-in mice with LoxP sites flanking exons encoding the critical ATPase domain of ORC1. They show that ORC1 ablation in extraembryonic trophoblasts and hepatocytes failed to impede genome endoreduplication and organ development and function and conclude that ORC1 in mice is essential for mitotic cell divisions but dispensable for endoreduplication. The largest subunit of the origin recognition complex (ORC1) is essential for assembly of the prereplicative complex, firing of DNA replication origins, and faithful duplication of the genome. Here, we generated knock-in mice with LoxP sites flanking exons encoding the critical ATPase domain of ORC1. Global or tissue-specific ablation of ORC1 function in mouse embryo fibroblasts and fetal and adult diploid tissues blocked DNA replication, cell lineage expansion, and organ development. Remarkably, ORC1 ablation in extraembryonic trophoblasts and hepatocytes, two polyploid cell types in mice, failed to impede genome endoreduplication and organ development and function. Thus, ORC1 in mice is essential for mitotic cell divisions but dispensable for endoreduplication. We propose that DNA replication of mammalian polyploid genomes uses a distinct ORC1-independent mechanism.
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Affiliation(s)
- Takayuki Okano-Uchida
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA
| | - Lindsey N Kent
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA
| | - Madhu M Ouseph
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Britney McCarty
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Jeffrey J Frank
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Raleigh Kladney
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Maria C Cuitino
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA
| | - John C Thompson
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Vincenzo Coppola
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, Ohio State University, Columbus, Ohio 43210, USA
| | - Maki Asano
- Solid Tumor Biology Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210, USA.,Department of Molecular Cellular and Biochemistry, Ohio State University, Columbus, Ohio 43210, USA
| | - Gustavo Leone
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA
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41
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Abstract
Polyploid cells, which contain multiple copies of the typically diploid genome, are widespread in plants and animals. Polyploidization can be developmentally programmed or stress induced, and arises from either cell-cell fusion or a process known as endoreplication, in which cells replicate their DNA but either fail to complete cytokinesis or to progress through M phase entirely. Polyploidization offers cells several potential fitness benefits, including the ability to increase cell size and biomass production without disrupting cell and tissue structure, and allowing improved cell longevity through higher tolerance to genomic stress and apoptotic signals. Accordingly, recent studies have uncovered crucial roles for polyploidization in compensatory cell growth during tissue regeneration in the heart, liver, epidermis and intestine. Here, we review current knowledge of the molecular pathways that generate polyploidy and discuss how polyploidization is used in tissue repair and regeneration.
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Affiliation(s)
| | - Bruce A Edgar
- Huntsman Cancer Institute, Salt Lake City, UT 84112, USA
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42
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Camm EJ, Botting KJ, Sferruzzi-Perri AN. Near to One's Heart: The Intimate Relationship Between the Placenta and Fetal Heart. Front Physiol 2018; 9:629. [PMID: 29997513 PMCID: PMC6029139 DOI: 10.3389/fphys.2018.00629] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/09/2018] [Indexed: 01/19/2023] Open
Abstract
The development of the fetal heart is exquisitely controlled by a multitude of factors, ranging from humoral to mechanical forces. The gatekeeper regulating many of these factors is the placenta, an external fetal organ. As such, resistance within the placental vascular bed has a direct influence on the fetal circulation and therefore, the developing heart. In addition, the placenta serves as the interface between the mother and fetus, controlling substrate exchange and release of hormones into both circulations. The intricate relationship between the placenta and fetal heart is appreciated in instances of clinical placental pathology. Abnormal umbilical cord insertion is associated with congenital heart defects. Likewise, twin-to-twin transfusion syndrome, where monochorionic twins have unequal sharing of their placenta due to inter-twin vascular anastomoses, can result in cardiac remodeling and dysfunction in both fetuses. Moreover, epidemiological studies have suggested a link between placental phenotypic traits and increased risk of cardiovascular disease in adult life. To date, the mechanistic basis of the relationships between the placenta, fetal heart development and later risk of cardiac dysfunction have not been fully elucidated. However, studies using environmental exposures and gene manipulations in experimental animals are providing insights into the pathways involved. Likewise, surgical instrumentation of the maternal and fetal circulations in large animal species has enabled the manipulation of specific humoral and mechanical factors to investigate their roles in fetal cardiac development. This review will focus on such studies and what is known to date about the link between the placenta and heart development.
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Affiliation(s)
- Emily J Camm
- Department of Physiology, Development and Neuroscience and Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
| | - Kimberley J Botting
- Department of Physiology, Development and Neuroscience and Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
| | - Amanda N Sferruzzi-Perri
- Department of Physiology, Development and Neuroscience and Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
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43
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Intrauterine smoke exposure deregulates lung function, pulmonary transcriptomes, and in particular insulin-like growth factor (IGF)-1 in a sex-specific manner. Sci Rep 2018; 8:7547. [PMID: 29765129 PMCID: PMC5953988 DOI: 10.1038/s41598-018-25762-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 04/30/2018] [Indexed: 12/13/2022] Open
Abstract
Prenatal exposure to tobacco smoke is a significant risk-factor for airway disease development. Furthermore, the high prevalence of pregnant smoking women requires the establishment of strategies for offspring lung protection. Therefore, we here aimed to understand the molecular mechanism of how prenatal smoke exposure affects fetal lung development. We used a mouse model recapitulating clinical findings of prenatally exposed children, where pregnant mice were exposed to smoke until c-section or spontaneous delivery, and offspring weight development and lung function was monitored. Additionally, we investigated pulmonary transcriptome changes in fetal lungs (GD18.5) by mRNA/miRNA arrays, network analyses and qPCR. The results demonstrated that prenatally exposed mice showed intrauterine and postnatal growth retardation, and impaired lung function. 1340 genes and 133 miRNAs were found to be significantly dysregulated by in utero smoke exposure, and we identified Insulin-like growth factor 1 (Igf1) as a top hierarchical node in a network analysis. Moreover, Igf1 mRNA was increased in female murine offspring and in prenatally exposed children. These findings suggest that prenatal smoking is associated with a dysregulation of several genes, including Igf1 in a sex-specific manner. Thus, our results could represent a novel link between smoke exposure, abberant lung development and impaired lung function.
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44
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Ye L, Guo L, He Z, Wang X, Lin C, Zhang X, Wu S, Bao Y, Yang Q, Song L, Lin H. Upregulation of E2F8 promotes cell proliferation and tumorigenicity in breast cancer by modulating G1/S phase transition. Oncotarget 2018; 7:23757-71. [PMID: 26992224 PMCID: PMC5029661 DOI: 10.18632/oncotarget.8121] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 02/25/2016] [Indexed: 01/04/2023] Open
Abstract
E2F transcription factors are involved in cell cycle regulation and synthesis of DNA in mammalian cells, and simultaneously play important roles in the development and progression of cancer when dysregulated. E2F8, a novel identified E2F family member, was found to be associated with the progression of several human cancers; however, the biological role and clinical significance of E2F8 in breast cancer remain to be further elucidated. Herein, we report that E2F8 is robustly elevated in breast cancer cell lines and clinical breast cancer tissue samples, respectively. The high expression level of E2F8 significantly correlates with clinical progression (P = 0.001), poor patient survival (P < 0.001) and a high Ki67 staining index (P = 0.008) in 187 human breast cancer specimens. Furthermore, we find that overexpressing E2F8 promotes, whereas silencing E2F8 suppresses, the proliferation and tumorigenicity of breast cancer cells both in vitro and in vivo. We further demonstrate that E2F8 transcriptionally upregulates CCNE1 and CCNE2 via directly interacting with their respective gene promoter, which accelerates the transition of G1 to S phase of breast cancer cells. Taken together, these findings uncover a novel biologic role and regulatory mechanism of E2F8 responsible for the progression of breast cancer, indicating E2F8 may represent a novel prognostic biomarker and therapeutic target against breast cancer.
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Affiliation(s)
- Liping Ye
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Ling Guo
- Department of Nasopharyngeal Carcinoma, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Zhenyu He
- Department of Radiation Oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Xi Wang
- Department of Breast Surgery, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Chuyong Lin
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Xin Zhang
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Shu Wu
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Yong Bao
- Department of Radiation Oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Qi Yang
- Department of Nasopharyngeal Carcinoma, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Libing Song
- Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Huanxin Lin
- Department of Radiation Oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
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45
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Atypical E2f functions are critical for pancreas polyploidization. PLoS One 2018; 13:e0190899. [PMID: 29329320 PMCID: PMC5766144 DOI: 10.1371/journal.pone.0190899] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 12/21/2017] [Indexed: 02/06/2023] Open
Abstract
The presence of polyploid cells in the endocrine and exocrine pancreas has been reported for four decades. In rodents, pancreatic polyploidization is initiated after weaning and the number of polyploid cells increases with age. Surprisingly the molecular regulators and biological functions of polyploidization in the pancreas are still unknown. We discovered that atypical E2f activity is essential for polyploidization in the pancreas, using an inducible Cre/LoxP approach in new-born mice to delete ubiquitously the atypical E2f transcription factors, E2f7 and E2f8. In contrast to its critical role in embryonic survival, conditional deletion of both of both atypical E2fs in newborn mice had no impact on postnatal survival and mice lived until old age. However, deficiency of E2f7 or E2f8 alone was sufficient to suppress polyploidization in the pancreas and associated with only a minor decrease in blood serum levels of glucose, insulin, amylase and lipase under 4 hours starvation condition compared to wildtype littermates. In mice with fewer pancreatic polyploid cells that were fed ad libitum, no major impact on hormones or enzymes levels was observed. In summary, we identified atypical E2fs to be essential for polyploidization in the pancreas and discovered that postnatal induced loss of both atypical E2fs in many organs is compatible with life until old age.
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46
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Guarner A, Morris R, Korenjak M, Boukhali M, Zappia MP, Van Rechem C, Whetstine JR, Ramaswamy S, Zou L, Frolov MV, Haas W, Dyson NJ. E2F/DP Prevents Cell-Cycle Progression in Endocycling Fat Body Cells by Suppressing dATM Expression. Dev Cell 2017; 43:689-703.e5. [PMID: 29233476 PMCID: PMC5901703 DOI: 10.1016/j.devcel.2017.11.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 08/28/2017] [Accepted: 11/07/2017] [Indexed: 10/18/2022]
Abstract
To understand the consequences of the complete elimination of E2F regulation, we profiled the proteome of Drosophila dDP mutants that lack functional E2F/DP complexes. The results uncovered changes in the larval fat body, a differentiated tissue that grows via endocycles. We report an unexpected mechanism of E2F/DP action that promotes quiescence in this tissue. In the fat body, dE2F/dDP limits cell-cycle progression by suppressing DNA damage responses. Loss of dDP upregulates dATM, allowing cells to sense and repair DNA damage and increasing replication of loci that are normally under-replicated in wild-type tissues. Genetic experiments show that ectopic dATM is sufficient to promote DNA synthesis in wild-type fat body cells. Strikingly, reducing dATM levels in dDP-deficient fat bodies restores cell-cycle control, improves tissue morphology, and extends animal development. These results show that, in some cellular contexts, dE2F/dDP-dependent suppression of DNA damage signaling is key for cell-cycle control and needed for normal development.
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Affiliation(s)
- Ana Guarner
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13(th) Street, Charlestown, MA 02129, USA
| | - Robert Morris
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13(th) Street, Charlestown, MA 02129, USA
| | - Michael Korenjak
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13(th) Street, Charlestown, MA 02129, USA
| | - Myriam Boukhali
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13(th) Street, Charlestown, MA 02129, USA
| | - Maria Paula Zappia
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 S Ashland Avenue, Chicago, IL 60607, USA
| | - Capucine Van Rechem
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13(th) Street, Charlestown, MA 02129, USA
| | - Johnathan R Whetstine
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13(th) Street, Charlestown, MA 02129, USA
| | - Sridhar Ramaswamy
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13(th) Street, Charlestown, MA 02129, USA
| | - Lee Zou
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13(th) Street, Charlestown, MA 02129, USA
| | - Maxim V Frolov
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 S Ashland Avenue, Chicago, IL 60607, USA
| | - Wilhelm Haas
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13(th) Street, Charlestown, MA 02129, USA
| | - Nicholas J Dyson
- Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13(th) Street, Charlestown, MA 02129, USA.
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47
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Lv Y, Xiao J, Liu J, Xing F. E2F8 is a Potential Therapeutic Target for Hepatocellular Carcinoma. J Cancer 2017; 8:1205-1213. [PMID: 28607595 PMCID: PMC5463435 DOI: 10.7150/jca.18255] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/11/2017] [Indexed: 12/15/2022] Open
Abstract
E2F transcriptional factors are widely expressed in a number of tissues and organs, possessing many regulatory functions related to cellular proliferation, differentiation, DNA repair, cell-cycle and cell apoptosis. E2F8 is a recently identified member of the E2F family with a duplicated DNA-binding domain feature discriminated from E2F1-6, controlling gene expression in a dimerization partner-independent manner. It is indispensable for angiogenesis, lymphangiogenesis and embryonic development. Although E2F8 and E2F7 perform complementary and overlapping functions in many cell metabolisms, E2F8, but not E2F7, overexpresses remarkably in hepatocellular carcinoma (HCC) to facilitate the HCC occurrence and development via activating a E2F1/ Cyclin D1 signaling pathway to regulate the G1- to S-phase transition of cell cycle progression or transcriptionally suppressing CDK1 to induce hepatocyte polyploidization. It also involves closely a variety of cellular physiological functions and pathological processes, which may bring a new breakthrough for the treatment of certain diseases, especially the HCC. Here, we summarize the latest progress of E2F8 on its relevant functions and mechanisms as well as potential application.
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Affiliation(s)
- Yi Lv
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China.,Key Laboratory of Functional Protein Research of Guangdong, Higher Education Institutes, Jinan University, Guangzhou, China
| | - Jia Xiao
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - Jing Liu
- Department of Stomatology, Jinan University, Guangzhou, China
| | - Feiyue Xing
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China.,Key Laboratory of Functional Protein Research of Guangdong, Higher Education Institutes, Jinan University, Guangzhou, China
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Kasak L, Rull K, Sõber S, Laan M. Copy number variation profile in the placental and parental genomes of recurrent pregnancy loss families. Sci Rep 2017; 7:45327. [PMID: 28345611 PMCID: PMC5366903 DOI: 10.1038/srep45327] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 02/23/2017] [Indexed: 12/25/2022] Open
Abstract
We have previously shown an extensive load of somatic copy number variations (CNVs) in the human placental genome with the highest fraction detected in normal term pregnancies. Hereby, we hypothesized that insufficient promotion of CNVs may impair placental development and lead to recurrent pregnancy loss (RPL). RPL affects ~3% of couples aiming at childbirth and idiopathic RPL represents ~50% of cases. We analysed placental and parental CNV profiles of idiopathic RPL trios (mother-father-placenta) and duos (mother-placenta). Consistent with the hypothesis, the placental genomes of RPL cases exhibited 2-fold less CNVs compared to uncomplicated 1st trimester pregnancies (P = 0.02). This difference mainly arose from lower number of duplications. Overall, 1st trimester control placentas shared only 5.3% of identified CNV regions with RPL cases, whereas the respective fraction with term placentas was 35.1% (P = 1.1 × 10−9). Disruption of the genes NUP98 (embryonic stem cell development) and MTRR (folate metabolism) was detected exclusively in RPL placentas, potentially indicative to novel loci implicated in RPL. Interestingly, genes with higher overall expression were prone to deletions (>3-fold higher median expression compared to genes unaffected by CNVs, P = 6.69 × 10−20). Additionally, large pericentromeric and subtelomeric CNVs in parental genomes emerged as a risk factor for RPL.
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Affiliation(s)
- Laura Kasak
- Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Riia 23 St., Tartu 51010, Estonia
| | - Kristiina Rull
- Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Riia 23 St., Tartu 51010, Estonia.,Department of Obstetrics and Gynaecology, University of Tartu, Puusepa St. 8, Tartu 51014, Estonia.,Women's Clinic of Tartu University Hospital, Puusepa St. 8, Tartu 51014, Estonia
| | - Siim Sõber
- Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Riia 23 St., Tartu 51010, Estonia.,Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila St. 19, Tartu 51014, Estonia
| | - Maris Laan
- Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Riia 23 St., Tartu 51010, Estonia.,Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila St. 19, Tartu 51014, Estonia
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Sun J, Shi R, Zhao S, Li X, Lu S, Bu H, Ma X, Su C. E2F8, a direct target of miR-144, promotes papillary thyroid cancer progression via regulating cell cycle. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:40. [PMID: 28270228 PMCID: PMC5341194 DOI: 10.1186/s13046-017-0504-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Accepted: 02/16/2017] [Indexed: 12/27/2022]
Abstract
Background Thyroid cancer is the most common malignancy of endocrine system, and papillary thyroid cancer (PTC) is the most common subtype. E2F8, a novel identified E2F family member, was reported to associate with progression of several human cancers, however, its clinical significance and biological role in PTC remain unknown. Methods E2F8 or miR-144 expression profiles in PTC tissues were obtained from The Cancer Genome Atlas (TCGA) datasets, and the correlation of E2F8 expression with clinicopathological features was analyzed in a cohort PTC patients. The effects of E2F8 and miR-144 on proliferation were evaluated both in vitro and in vivo. Luciferase reporter assay was used to determine E2F8 was a direct target of miR-144. Results E2F8 was widely upregulated in PTC tissues, and overexpression of E2F8 was correlated with more aggressive clinicopathological features. In contrast, we found that silence of E2F8 significantly suppressed proliferation of PTC cells by inducing G1-phase arrest via downregulating Cyclin D1 (CCND1) both in vitro and in vivo. We also identified miR-144 as a tumor-suppressive microRNA that directly targeted E2F8 to inhibit proliferation of PTC cells in vitro and in vivo. Moreover, miR-144 was widely downregulated in PTC, where its expression correlated inversely with E2F8 expression. Conclusions Our results demonstrate a new miR-144/E2F8/CCND1 regulatory axis controlling PTC development, which may offer a potential prognostic and therapeutic strategy. Trial registration No applicable. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0504-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jing Sun
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Run Shi
- The Fourth Clinical College of Nanjing Medical University, Hanzhong Road 140, Nanjing, 210029, China
| | - Sha Zhao
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Xiaona Li
- Health Management Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Shan Lu
- Department of Nutriology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Hemei Bu
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Xianghua Ma
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
| | - Chuan Su
- Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China.
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Kent LN, Bae S, Tsai SY, Tang X, Srivastava A, Koivisto C, Martin CK, Ridolfi E, Miller GC, Zorko SM, Plevris E, Hadjiyannis Y, Perez M, Nolan E, Kladney R, Westendorp B, de Bruin A, Fernandez S, Rosol TJ, Pohar KS, Pipas JM, Leone G. Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma. J Clin Invest 2017; 127:830-842. [PMID: 28134624 DOI: 10.1172/jci87583] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 12/06/2016] [Indexed: 12/21/2022] Open
Abstract
Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1- and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer.
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