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Liu S, Zhao L, Peng Y, Liu X, Yan W, Zhang L, Zhang J. Obesity induced caveolin-1 impairs osteogenesis via activating mitophagy and inhibiting Sirt1 signaling. Bone 2024; 186:117146. [PMID: 38844017 DOI: 10.1016/j.bone.2024.117146] [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: 09/24/2023] [Revised: 06/01/2024] [Accepted: 06/03/2024] [Indexed: 07/08/2024]
Abstract
Obesity has become a major global health problem and the effect on bone formation has received increasing attention. However, the interaction between obesity and bone metabolism is complex and still not fully understood. Here, we show that caveolin-1 (Cav1), a membrane scaffold protein involved in regulating a variety of cellular processes, plays a key regulatory role as a bridge connecting obesity and bone metabolism. High-fat diet (HFD)-induced obese C57BL/6J mouse displayed a significant increase in Cav1 expression and lower osteogenic activity; In vitro treatment of osteoblastic MC3T3-E1 cells with 1 mM free fatty acids (FFA) significantly promoted Cav1 expression and PINK1/Parkin regulated mitophagy, but inhibited the expression of osteogenic marker genes. Conversely, reduced expression of the Cav1 gene prevented these effects. Both endogenous oxidative stress and Sirt1 pathway were also significantly reduced after Cav1 knockdown in FFA-treated cells. Finally, Cav1-Sirt1 docking and co-immunoprecipitation results showed that Cav1 interacted with Sirt1 and FFA enhanced the interaction. Taken together, these results suggest that obesity impairs bone development and formation through up-regulation of the Cav1 gene, which lead to inhibition of Sirt1/FOXO1 and Sirt1/PGC-1α signaling pathways through interacting with Sirt1 molecule, and an increase of mitophagy level.
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Affiliation(s)
- Shuai Liu
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Lixia Zhao
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Yanqiu Peng
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Xing Liu
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Wenmin Yan
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Lizi Zhang
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China
| | - Jian Zhang
- Bioengineering College, Zhuhai campus of Zunyi Medical University, Zhuhai, Guangdong, China.
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2
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Liu M, Xing Y, Tan J, Chen X, Xue Y, Qu L, Ma J, Jin X. Comprehensive summary: the role of PBX1 in development and cancers. Front Cell Dev Biol 2024; 12:1442052. [PMID: 39129784 PMCID: PMC11310070 DOI: 10.3389/fcell.2024.1442052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 07/16/2024] [Indexed: 08/13/2024] Open
Abstract
PBX1 is a transcription factor that can promote the occurrence of various tumors and play a reg-ulatory role in tumor growth, metastasis, invasion, and drug resistance. Furthermore, a variant generated by fusion of E2A and PBX1, E2A-PBX1, has been found in 25% of patients with childhood acute lymphoblastic leukemia. Thus, PBX1 is a potential therapeutic target for many cancers. Here, we describe the structure of PBX1 and E2A-PBX1 as well as the molecular mecha-nisms whereby these proteins promote tumorigenesis to provide future research directions for developing new treatments. We show that PBX1 and E2A-PBX1 induce the development of highly malignant and difficult-to-treat solid and blood tumors. The development of specific drugs against their targets may be a good therapeutic strategy for PBX1-related cancers. Furthermore, we strongly recommend E2A-PBX1 as one of the genes for prenatal screening to reduce the incidence of childhood hematological malignancies.
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Affiliation(s)
- Mingsheng Liu
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Yan Xing
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Jiufeng Tan
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Xiaoliang Chen
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Yaming Xue
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Licheng Qu
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Jianchao Ma
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
| | - Xuefei Jin
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital, Jilin University, Changchun, China
- Jinlin Provincial Key Laboratory of Molecular Diagnosis of Urological Tumors, Changchun, China
- Jinlin Provincial Key Laboratory of Urological Tumors, Changchun, China
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Dashti P, Lewallen EA, Gordon JAR, Montecino MA, Davie JR, Stein GS, van Leeuwen JPTM, van der Eerden BCJ, van Wijnen AJ. Epigenetic regulators controlling osteogenic lineage commitment and bone formation. Bone 2024; 181:117043. [PMID: 38341164 DOI: 10.1016/j.bone.2024.117043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/08/2024] [Accepted: 02/04/2024] [Indexed: 02/12/2024]
Abstract
Bone formation and homeostasis are controlled by environmental factors and endocrine regulatory cues that initiate intracellular signaling pathways capable of modulating gene expression in the nucleus. Bone-related gene expression is controlled by nucleosome-based chromatin architecture that limits the accessibility of lineage-specific gene regulatory DNA sequences and sequence-specific transcription factors. From a developmental perspective, bone-specific gene expression must be suppressed during the early stages of embryogenesis to prevent the premature mineralization of skeletal elements during fetal growth in utero. Hence, bone formation is initially inhibited by gene suppressive epigenetic regulators, while other epigenetic regulators actively support osteoblast differentiation. Prominent epigenetic regulators that stimulate or attenuate osteogenesis include lysine methyl transferases (e.g., EZH2, SMYD2, SUV420H2), lysine deacetylases (e.g., HDAC1, HDAC3, HDAC4, HDAC7, SIRT1, SIRT3), arginine methyl transferases (e.g., PRMT1, PRMT4/CARM1, PRMT5), dioxygenases (e.g., TET2), bromodomain proteins (e.g., BRD2, BRD4) and chromodomain proteins (e.g., CBX1, CBX2, CBX5). This narrative review provides a broad overview of the covalent modifications of DNA and histone proteins that involve hundreds of enzymes that add, read, or delete these epigenetic modifications that are relevant for self-renewal and differentiation of mesenchymal stem cells, skeletal stem cells and osteoblasts during osteogenesis.
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Affiliation(s)
- Parisa Dashti
- Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Eric A Lewallen
- Department of Biological Sciences, Hampton University, Hampton, VA, USA
| | | | - Martin A Montecino
- Institute of Biomedical Sciences, Faculty of Medicine, Universidad Andres Bello, Santiago, Chile; Millennium Institute Center for Genome Regulation (CRG), Santiago, Chile
| | - James R Davie
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada; CancerCare Manitoba Research Institute, CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada.
| | - Gary S Stein
- Department of Biochemistry, University of Vermont, Burlington, VT, USA
| | | | - Bram C J van der Eerden
- Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, Netherlands.
| | - Andre J van Wijnen
- Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Biochemistry, University of Vermont, Burlington, VT, USA.
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Kao TW, Chen HH, Lin J, Wang TL, Shen YA. PBX1 as a novel master regulator in cancer: Its regulation, molecular biology, and therapeutic applications. Biochim Biophys Acta Rev Cancer 2024; 1879:189085. [PMID: 38341110 DOI: 10.1016/j.bbcan.2024.189085] [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: 10/20/2023] [Revised: 01/31/2024] [Accepted: 02/05/2024] [Indexed: 02/12/2024]
Abstract
PBX1 is a critical transcription factor at the top of various cell fate-determining pathways. In cancer, PBX1 stands at the crossroads of multiple oncogenic signaling pathways and mediates responses by recruiting a broad repertoire of downstream targets. Research thus far has corroborated the involvement of PBX1 in cancer proliferation, resisting apoptosis, tumor-associated neoangiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, immune evasion, genome instability, and dysregulating cellular metabolism. Recently, our understanding of the functional regulation of the PBX1 protein has advanced, as increasing evidence has depicted a regulatory network consisting of transcriptional, post-transcriptional, and post-translational levels of control mechanisms. Furthermore, accumulating studies have supported the clinical utilization of PBX1 as a prognostic or therapeutic target in cancer. Preliminary results showed that PBX1 entails vast potential as a targetable master regulator in the treatment of cancer, particularly in those with high-risk features and resistance to other therapeutic strategies. In this review, we will explore the regulation, protein-protein interactions, molecular pathways, clinical application, and future challenges of PBX1.
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Affiliation(s)
- Ting-Wan Kao
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan
| | - Hsiao-Han Chen
- Department of General Medicine, National Taiwan University Hospital, Taipei 100224, Taiwan
| | - James Lin
- School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan
| | - Tian-Li Wang
- Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB2, Room 306, Baltimore, MD 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Yao-An Shen
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan; International Master/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan.
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Crisafulli L, Brindisi M, Liturri MG, Sobacchi C, Ficara F. PBX1: a TALE of two seasons-key roles during development and in cancer. Front Cell Dev Biol 2024; 12:1372873. [PMID: 38404687 PMCID: PMC10884236 DOI: 10.3389/fcell.2024.1372873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 01/29/2024] [Indexed: 02/27/2024] Open
Abstract
Pre-B cell leukemia factor 1 (PBX1) is a Three Aminoacid Loop Extension (TALE) homeodomain-containing transcription factor playing crucial roles in organ pattering during embryogenesis, through the formation of nuclear complexes with other TALE class and/or homeobox proteins to regulate target genes. Its contribution to the development of several organs has been elucidated mainly through the study of murine knockout models. A crucial role for human development has been recently highlighted through the discovery of different de novo pathogenic PBX1 variants in children affected by developmental defects. In the adult, PBX1 is expressed in selected tissues such as in the brain, in the gastro-intestinal and urinary systems, or in hematopoietic stem and progenitor cells, while in other organs is barely detectable. When involved in the t(1;19) chromosomal translocation it acts as an oncogene, since the resulting fusion protein drives pre-B cell leukemia, due to the induction of target genes not normally targeted by the native protein. Its aberrant expression has been associated to tumor development, progression, or therapy-resistance as in breast cancer, ovarian cancer or myeloproliferative neoplasm (MPN). On the other hand, in colorectal cancer PBX1 functions as a tumor suppressor, highlighting its context-dependent role. We here discuss differences and analogies of PBX1 roles during embryonic development and in cancer, focusing mainly on the most recent discoveries.
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Affiliation(s)
- Laura Crisafulli
- IRCCS Humanitas Research Hospital, Milan, Italy
- Milan Unit, Istituto di Ricerca Genetica e Biomedica (IRGB), National Research Council, Milan, Italy
| | - Matteo Brindisi
- IRCCS Humanitas Research Hospital, Milan, Italy
- Milan Unit, Istituto di Ricerca Genetica e Biomedica (IRGB), National Research Council, Milan, Italy
| | | | - Cristina Sobacchi
- IRCCS Humanitas Research Hospital, Milan, Italy
- Milan Unit, Istituto di Ricerca Genetica e Biomedica (IRGB), National Research Council, Milan, Italy
| | - Francesca Ficara
- IRCCS Humanitas Research Hospital, Milan, Italy
- Milan Unit, Istituto di Ricerca Genetica e Biomedica (IRGB), National Research Council, Milan, Italy
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Liu Z, Zhang N, Xin B, Shi Y, Liang Z, Wan Y, Hu X. Exosomes from LSD1 knockdown breast cancer cells activate osteoclastogenesis and inhibit osteoblastogenesis. Int J Biol Macromol 2023; 235:123792. [PMID: 36828097 DOI: 10.1016/j.ijbiomac.2023.123792] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 02/07/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023]
Abstract
Bone metastasis is a common and incurable complication of breast cancer. Lysine-specific demethylase 1 (LSD1), a histone demethylase, plays an important role in the metastasis of breast cancer. However, the role of LSD1 in bone metastasis of breast cancer is unclear. We hypothesized that exosomes from LSD1 knockdown breast cancer cells promote bone metastasis by remodeling bone microenvironment. To verify this hypothesis, exosomes from LSD1 knockdown Estrogen receptor-positive cancer cell lines, MCF7 and T47D, were isolated, and the effects of these exosomes on osteoblast and osteoclast differentiation were investigated. Interestingly, exosomes from LSD1 knockdown breast cancer cells inhibited osteoblast differentiation and promoted osteoclast differentiation. Mechanistically, miR-6881-3p was decreased in the exosomes from LSD1 knockdown cells, and miR-6881-3p suppressed the expression of pre-B-cell leukemia homeobox 1 (PBX1) and additional sex combs like-2 (ASXL2), two genes with essential functions in osteoblast and osteoclast differentiations respectively. Transfection of miR-6881-3p into LSD1 knockdown cells reversed the effects of the exosomes on osteoblast and osteoclast differentiations. Our study reveals important roles of LSD1 on the regulation of exosomal miRNAs and the formation of favorable bone microenvironment for metastasis.
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Affiliation(s)
- Ziyu Liu
- China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China; School of Life Sciences, Jilin University, Changchun, Jilin 130012, China
| | - Nan Zhang
- China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China
| | - Benkai Xin
- China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China
| | - Yueru Shi
- China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China
| | - Zehua Liang
- China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China
| | - Youzhong Wan
- China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China
| | - Xin Hu
- China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China.
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7
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Gopinathan G, Luan X, Diekwisch TGH. Epigenetic Repression of RUNX2 and OSX Promoters Controls the Nonmineralized State of the Periodontal Ligament. Genes (Basel) 2023; 14:201. [PMID: 36672941 PMCID: PMC9858805 DOI: 10.3390/genes14010201] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 01/13/2023] Open
Abstract
The nonmineralized state of the mammalian periodontal ligament is one of the hallmarks of vertebrate evolution as it provides resilient and nontraumatic tooth anchorage for effective predation. Here we sought to determine how the chromatin state of key mineralization gene promoters contributes to the nonmineralized periodontal ligament in the midst of fully mineralized alveolar bone and cementum anchor tissues. In developing mouse periodontal tissues, RUNX2 was localized to alveolar bone-lining cells, while OSX was localized throughout the periodontal ligament's soft tissue. Matching RT-PCR amplification data and western blot comparisons demonstrated that the expression of RUNX2 and OSX bone mineralization transcription factors was at least 2.5-fold elevated in alveolar bone osteoblasts versus periodontal ligament fibroblasts. ChIP enrichment data along the RUNX2 and OSX promoters revealed increased H3K4me3 marks in alveolar bone osteoblasts, while H3K9me3 and H3K27me3 marks were elevated in periodontal ligament fibroblasts. In support of an epigenetic mechanism responsible for the inhibition of mineralization gene expression in periodontal progenitors, histone methylation inhibitors DZNep and Chaetocin reactivated RUNX2 and OSX expression in periodontal progenitors and increased alkaline phosphatase and Alizarin Red, while the in vivo application of DZNep in rat maxillae resulted in aberrant mineralization in the periodontal ligament and a narrowing of the nonmineralized periodontal space. Together, these studies demonstrate that the nonmineralized state of the mammalian periodontal ligament is controlled by an epigenetic regulation of the RUNX2 and OSX key mineralization gene promoters.
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Affiliation(s)
- Gokul Gopinathan
- Center for Craniofacial Research and Diagnosis, Texas A&M University College of Dentistry, Dallas, TX 75246, USA
| | - Xianghong Luan
- Center for Craniofacial Research and Diagnosis, Texas A&M University College of Dentistry, Dallas, TX 75246, USA
| | - Thomas G. H. Diekwisch
- Department of Oral and Craniofacial Sciences, University of Rochester School of Medicine and Dentistry, 625 Elmwood Avenue, Rochester, NY 14620, USA
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Chen H, Yu Z, Niu Y, Wang L, Xu K, Liu J. Research progress of PBX1 in developmental and regenerative medicine. Int J Med Sci 2023; 20:225-231. [PMID: 36794159 PMCID: PMC9925990 DOI: 10.7150/ijms.80262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 01/10/2023] [Indexed: 02/04/2023] Open
Abstract
Pre-B-cell leukemia transcription factor 1 (PBX1) proteins are a subfamily of evolutionarily conserved atypical homeodomain transcription factors belonging to the superfamily of triple amino acid loop extension homeodomain proteins. PBX family members play crucial roles in the regulation of various pathophysiological processes. This article reviews the research progress on PBX1 in terms of structure, developmental function, and regenerative medicine. The potential mechanisms of development and research targets in regenerative medicine are also summarized. It also suggests a possible link between PBX1 in the two domains, which is expected to open up a new field for future exploration of cell homeostasis, as well as the regulation of endogenous danger signals. This would provide a new target for the study of diseases in various systems.
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Affiliation(s)
- Hao Chen
- Department of Neurovascular Surgery, First Hospital of Jilin University, 1 Xinmin Avenue Changchun 130021, Jilin Province, China
| | - Zhuyuan Yu
- Department of Neurovascular Surgery, First Hospital of Jilin University, 1 Xinmin Avenue Changchun 130021, Jilin Province, China
| | - Ye Niu
- Department of Toxicology, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Litian Wang
- Department of Neurovascular Surgery, First Hospital of Jilin University, 1 Xinmin Avenue Changchun 130021, Jilin Province, China
| | - Kan Xu
- Department of Neurovascular Surgery, First Hospital of Jilin University, 1 Xinmin Avenue Changchun 130021, Jilin Province, China
| | - Jinyu Liu
- Department of Toxicology, School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
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Yin J, Xiao W, Zhao Q, Sun J, Zhou W, Zhao W. MicroRNA-582-3p regulates osteoporosis through regulating homeobox A10 and osteoblast differentiation. Immunopharmacol Immunotoxicol 2022; 44:421-428. [PMID: 35285389 DOI: 10.1080/08923973.2022.2052895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Jian Yin
- Department of Orthopedic, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, 830001, PR. China
| | - Wei Xiao
- Department of Orthopedic, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, 830001, PR. China
| | - Qingbin Zhao
- Department of Orthopedic, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, 830001, PR. China
| | - Jungang Sun
- Department of Orthopedic, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, 830001, PR. China
| | - Wenzheng Zhou
- Department of Orthopedic, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, 830001, PR. China
| | - Wei Zhao
- Department of Orthopedic, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, 830001, PR. China
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Epigenetic modifications of histones during osteoblast differentiation. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2022; 1865:194780. [PMID: 34968769 DOI: 10.1016/j.bbagrm.2021.194780] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/30/2021] [Accepted: 12/08/2021] [Indexed: 12/20/2022]
Abstract
In bone biology, epigenetics plays a key role in mesenchymal stem cells' (MSCs) commitment towards osteoblasts. It involves gene regulatory mechanisms governed by chromatin modulators. Predominant epigenetic mechanisms for efficient osteogenic differentiation include DNA methylation, histone modifications, and non-coding RNAs. Among these mechanisms, histone modifications critically contribute to altering chromatin configuration. Histone based epigenetic mechanisms are an essential mediator of gene expression during osteoblast differentiation as it directs the bivalency of the genome. Investigating the importance of histone modifications in osteogenesis may lead to the development of epigenetic-based remedies for genetic disorders of bone. Hence, in this review, we have highlighted the importance of epigenetic modifications such as post-translational modifications of histones, including methylation, acetylation, phosphorylation, ubiquitination, and their role in the activation or suppression of gene expression during osteoblast differentiation. Further, we have emphasized the future advancements in the field of epigenetics towards orthopaedical therapeutics.
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11
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Wang C, Li Y, Yu K, Jiang Z, Wang Y, Yang G. HOXA10 inhibit the osteogenic differentiation of periodontal ligament stem cells by regulating β-catenin localization and DKK1 expression. Connect Tissue Res 2021; 62:393-401. [PMID: 32299243 DOI: 10.1080/03008207.2020.1756271] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 04/09/2020] [Indexed: 02/06/2023]
Abstract
Introduction: Human periodontal ligament stem cells (hPDLSCs) are stem cells found near the tooth periodontal ligament. These cels are involved in the regeneration of the periodontal ligament and alveolar bone during orthodontic treatment and chronic periodontitis.Objectives: The Homeobox gene HOXA10 regulates the osteogenic differentiation of stem cells. However, the role of HOXA10 in hPDLSCs remains unclear. Therefore, we studied the effects of HOXA10 on human PDLSC osteogenic differentiation in vitro.Methods: First, hPDLSCs were isolated and characterized. Second, we assessed the effects of overexpression and knockdown of HOXA10 on PDLSC osteogenic differentiation. Finally, the specific Wnt signaling pathway activator lithium chloride (LiCl) and inhibitor ICG-001 were used to investigate the involvement of the Wnt signaling pathway in HOXA10-induced regulation of osteogenic differentiation.Results: Overexpressing HOXA10 inhibited PDLSC osteogenic differentiation in vitro, shown by ALP and Alizarin Red staining, while HOXA10 knockdown demonstrated the opposite effects. HOXA10 negatively regulated nuclear β-catenin and osteogenic differentiation markers including alkaline phosphatase (ALPL) and integrin-binding sialoprotein (IBSP). Upregulating HOXA10 reduced nuclear β-catenin and increased DKK1 expression. However, HOXA10 knockdown enhanced nuclear β-catenin accumulation and reduced DKK1 expression. These negative effects on osteogenic differentiation by HOXA10 overexpression were restored by the Wnt/β-catenin pathway activator LiCl. The increased osteogenic differentiation effects of HOXA10 knockdown were antagonized by ICG-001, a Wnt pathway inhibitor.Conclusion: These data demonstrate that HOXA10 inhibits the osteogenic differentiation of periodontal ligament stem cells by regulating β-catenin localization and DKK1.
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Affiliation(s)
- Chengze Wang
- The Affiliated Stomatology Hospital, Zhejiang University, School of Medicine, Hangzhou, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, Hangzhou, China
| | - Yongzheng Li
- The Affiliated Stomatology Hospital, Zhejiang University, School of Medicine, Hangzhou, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, Hangzhou, China
| | - Ke Yu
- The Affiliated Stomatology Hospital, Zhejiang University, School of Medicine, Hangzhou, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, Hangzhou, China
| | - Zhiwei Jiang
- The Affiliated Stomatology Hospital, Zhejiang University, School of Medicine, Hangzhou, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, Hangzhou, China
| | - Ying Wang
- The Affiliated Stomatology Hospital, Zhejiang University, School of Medicine, Hangzhou, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, Hangzhou, China
| | - Guoli Yang
- The Affiliated Stomatology Hospital, Zhejiang University, School of Medicine, Hangzhou, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, Hangzhou, China
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Yi SJ, Jang YJ, Kim HJ, Lee K, Lee H, Kim Y, Kim J, Hwang SY, Song JS, Okada H, Park JI, Kang K, Kim K. The KDM4B-CCAR1-MED1 axis is a critical regulator of osteoclast differentiation and bone homeostasis. Bone Res 2021; 9:27. [PMID: 34031372 PMCID: PMC8144413 DOI: 10.1038/s41413-021-00145-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 01/10/2021] [Accepted: 01/22/2021] [Indexed: 12/12/2022] Open
Abstract
Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Recent studies have shown that histone demethylases are implicated in osteoblastogenesis; however, little is known about the role of histone demethylases in osteoclast formation. Here, we identified KDM4B as an epigenetic regulator of osteoclast differentiation. Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency. Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex. Using genome-wide chromatin immunoprecipitation (ChIP)-sequencing, we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation. We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure (euchromatinization) near the promoters of osteoclast-related genes through H3K9 demethylation, leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65. Finally, small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model. Taken together, our findings establish KDM4B as a critical regulator of osteoclastogenesis, providing a potential therapeutic target for osteoporosis.
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Affiliation(s)
- Sun-Ju Yi
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - You-Jee Jang
- Korea Basic Science Institute, Gwangju Center at Chonnam National University, Gwangju, Republic of Korea
| | - Hye-Jung Kim
- New Drug Development Center, KBIO Osong Medical Innovation Foundation, Cheongju, Chungbuk, Republic of Korea
| | - Kyubin Lee
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Hyerim Lee
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Yeojin Kim
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Junil Kim
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Seon Young Hwang
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Jin Sook Song
- Data Convergence Drug Research Center, Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
| | - Hitoshi Okada
- Department of Biochemistry, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Jae-Il Park
- Korea Basic Science Institute, Gwangju Center at Chonnam National University, Gwangju, Republic of Korea
| | - Kyuho Kang
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyunghwan Kim
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
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13
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Hensley AP, McAlinden A. The role of microRNAs in bone development. Bone 2021; 143:115760. [PMID: 33220505 PMCID: PMC8019264 DOI: 10.1016/j.bone.2020.115760] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 11/06/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023]
Abstract
Epigenetic regulation is critical for proper bone development. Evidence from a large body of published literature informs us that microRNAs (miRNAs) are important epigenetic factors that control many aspects of bone development, homeostasis, and repair processes. These small non-coding RNAs function at the post-transcriptional level to suppress expression of specific target genes. Many target genes may be affected by one miRNA resulting in alteration in cellular pathways and networks. Therefore, changes in levels or activity of a specific miRNA (e.g. via genetic mutations, disease scenarios, or by over-expression or inhibition strategies in vitro or in vivo) can lead to substantial changes in cell processes including proliferation, metabolism, apoptosis and differentiation. In this review, Section 1 briefly covers general background information on processes that control bone development as well as the biogenesis and function of miRNAs. In Section 2, we discuss the importance of miRNAs in skeletal development based on findings from in vivo mouse models and human clinical reports. Section 3 focuses on describing more recent data from the last three years related to miRNA regulation of osteoblast differentiation in vitro. Some of these studies also involve utilization of an in vivo rodent model to study the effects of miRNA modulation in scenarios of osteoporosis, bone repair or ectopic bone formation. In Section 4, we provide some recent information from studies analyzing the potential of miRNA-mediated crosstalk in bone and how exosomes containing miRNAs from one bone cell may affect the differentiation or function of another bone cell type. We then conclude by summarizing where the field currently stands with respect to miRNA-mediated regulation of osteogenesis and how information gained from developmental processes can be instructive in identifying potential therapeutic miRNA targets for the treatment of certain bone conditions.
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Affiliation(s)
- Austin P Hensley
- Department of Biomedical Engineering, Washington University School of Medicine, St Louis, MO, United States of America
| | - Audrey McAlinden
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, United States of America; Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, United States of America; Shriners Hospital for Children - St Louis, St Louis, MO, United States of America.
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14
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Montecino M, Carrasco ME, Nardocci G. Epigenetic Control of Osteogenic Lineage Commitment. Front Cell Dev Biol 2021; 8:611197. [PMID: 33490076 PMCID: PMC7820369 DOI: 10.3389/fcell.2020.611197] [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: 09/28/2020] [Accepted: 12/11/2020] [Indexed: 12/22/2022] Open
Abstract
Within the eukaryotic nucleus the genomic DNA is organized into chromatin by stably interacting with the histone proteins as well as with several other nuclear components including non-histone proteins and non-coding RNAs. Together these interactions distribute the genetic material into chromatin subdomains which can exhibit higher and lower compaction levels. This organization contributes to differentially control the access to genomic sequences encoding key regulatory genetic information. In this context, epigenetic mechanisms play a critical role in the regulation of gene expression as they modify the degree of chromatin compaction to facilitate both activation and repression of transcription. Among the most studied epigenetic mechanisms we find the methylation of DNA, ATP-dependent chromatin remodeling, and enzyme-mediated deposition and elimination of post-translational modifications at histone and non-histone proteins. In this mini review, we discuss evidence that supports the role of these epigenetic mechanisms during transcriptional control of osteoblast-related genes. Special attention is dedicated to mechanisms of epigenetic control operating at the Runx2 and Sp7 genes coding for the two principal master regulators of the osteogenic lineage during mesenchymal stem cell commitment.
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Affiliation(s)
- Martin Montecino
- Faculty of Medicine and Faculty of Life Sciences, Institute of Biomedical Sciences and FONDAP Center for Genome Regulation, Universidad Andres Bello, Santiago, Chile
| | - Margarita E Carrasco
- Faculty of Medicine and Faculty of Life Sciences, Institute of Biomedical Sciences and FONDAP Center for Genome Regulation, Universidad Andres Bello, Santiago, Chile
| | - Gino Nardocci
- Faculty of Medicine, Universidad de los Andes, Santiago, Chile.,Molecular Biology and Bioinformatic Lab, Program in Molecular Biology and Bioinformatics, Center for Biomedical Research and Innovation (CIIB), Universidad de los Andes, Santiago, Chile
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15
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Busby T, Chen Y, Godfrey TC, Rehan M, Wildman BJ, Smith CM, Hassan Q. Baf45a Mediated Chromatin Remodeling Promotes Transcriptional Activation for Osteogenesis and Odontogenesis. Front Endocrinol (Lausanne) 2021; 12:763392. [PMID: 35046892 PMCID: PMC8762305 DOI: 10.3389/fendo.2021.763392] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/06/2021] [Indexed: 11/13/2022] Open
Abstract
Chromatin remodeling, specifically the tissue-specific regulation in mineralized tissues, is an understudied avenue of gene regulation. Here we show that Baf45a and Baf45d, two Baf45 homologs belong to ATPase-dependent SWI/SNF chromatin remodeling complex, preferentially expressed in osteoblasts and odontoblasts compared to Baf45b and Baf45c. Recently, biochemical studies revealed that BAF45A associates with Polybromo-associated BAF (PBAF) complex. However, the BAF45D subunit belongs to the polymorphic canonical BRG1-associated factor (cBAF) complex. Protein profiles of osteoblast and odontoblast differentiation uncovered a significant increase of BAF45A and PBAF subunits during early osteoblast and odontoblast maturation. Chromatin immunoprecipitation sequencing (ChIP-seq) during the bone marrow stromal cells (BMSCs) differentiation showed higher histone H3K9 and H3K27 acetylation modifications in the promoter of Baf45a and Baf45d and increased binding of bone and tooth specific transcription factor RUNX2. Overexpression of Baf45a in osteoblasts activates genes essential for the progression of osteoblast maturation and mineralization. Furthermore, shRNA-mediated knockdown of Baf45a in odontoblasts leads to markedly altered genes responsible for the proliferation, apoptosis, DNA repair, and modest decrease in dentinogenic marker gene expression. Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) assay in Baf45a knockout osteoblasts revealed a noticeable reduction in chromatin accessibility of osteoblast and odontoblast specific genes, along with transcription factor Atf4 and Klf4. Craniofacial mesenchyme-specific loss of Baf45a modestly reduced the mineralization of the tooth and mandibular bone. These findings indicated that BAF45A-dependent mineralized tissue-specific chromatin remodeling through PBAF-RUNX2 crosstalk results in transcriptional activation is critical for early differentiation and matrix maturation of mineralized tissues.
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16
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Ramalho L, Nedjari S, Guarino R, Awaja F, Gugutkov D, Altankov G. Fibronectin/thermo-responsive polymer scaffold as a dynamic ex vivo niche for mesenchymal stem cells. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2020; 31:129. [PMID: 33252710 DOI: 10.1007/s10856-020-06461-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 10/31/2020] [Indexed: 06/12/2023]
Abstract
In this paper, we created a dynamic adhesive environment (DAE) for adipose tissue-derived mesenchymal stem cells (ADMSCs) cultured on smart thermo-responsive substrates, i.e., poly (N-isopropyl acrylamide) (PNIPAM), via introducing periodic changes in the culture temperature. We further explored the particular role of adsorbed fibronectin (FN), an important cell adhesive protein that was recently attributed to the recruitment of stem cells in the niche. The engineered FN/PNIPAM DAE system significantly increased the symmetric renewal of ADMSCs, particularly between passages 7 and 9 (p7-p9), before it dropped down to the level of the control (FN-coated TC polystyrene). This decline in the growth curve was consistent with the increased number of senescent cells, the augmented average cell size and the suppressed FN matrix secretion at late passages (p10-p12), all of them characteristic for stem cells ageing, which equivocally tended to slow down at our DAE system. FN supported also the osteogenic response of ADMSCs (apart from the previous observations with plain PNIPAM substrata) indicated by the significant increase of alkaline phosphatase (ALP) activity at days 7 and 14. The minimal changes in the Ca deposition, however, suggest a restricted effect of DAE on the early osteogenic response of ADMSCs only. Thus, the engineering of niche-like DAE involving FN uncovers a new tissue engineering strategy for gaining larger amounts of functionally active stem cells for clinical application.
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Affiliation(s)
- Laura Ramalho
- ICREA, Barcelona, Spain
- Institute of Biophysics and Biomedical Engineering, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
| | | | - Roberto Guarino
- École Polytechnique Fédérale de Lausanne (EPFL), Swiss Plasma Center (SPC), CH-5232, Villigen PSI, Switzerland
| | - Firas Awaja
- Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain
- Engmat Ltd., Clybaun Road, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) and Centre for Research in Medical Devices (CÚRAM) at National University of Ireland, Galway, Ireland
| | | | - George Altankov
- ICREA, Barcelona, Spain.
- Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain.
- Associate Member Institute for Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria.
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17
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Ghorbaninejad M, Khademi-Shirvan M, Hosseini S, Baghaban Eslaminejad M. Epidrugs: novel epigenetic regulators that open a new window for targeting osteoblast differentiation. Stem Cell Res Ther 2020; 11:456. [PMID: 33115508 PMCID: PMC7594482 DOI: 10.1186/s13287-020-01966-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/05/2020] [Indexed: 01/01/2023] Open
Abstract
Efficient osteogenic differentiation of mesenchymal stem cells (MSCs) is a critical step in the treatment of bone defects and skeletal disorders, which present challenges for cell-based therapy and regenerative medicine. Thus, it is necessary to understand the regulatory agents involved in osteogenesis. Epigenetic mechanisms are considered to be the primary mediators that regulate gene expression during MSC differentiation. In recent years, epigenetic enzyme inhibitors have been used as epidrugs in cancer therapy. A number of studies mentioned the role of epigenetic inhibitors in the regulation of gene expression patterns related to osteogenic differentiation. This review attempts to provide an overview of the key regulatory agents of osteogenesis: transcription factors, signaling pathways, and, especially, epigenetic mechanisms. In addition, we propose to introduce epigenetic enzyme inhibitors (epidrugs) and their applications as future therapeutic approaches for bone defect regeneration.
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Affiliation(s)
- Mahsa Ghorbaninejad
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Maliheh Khademi-Shirvan
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Samaneh Hosseini
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. .,Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Mohamadreza Baghaban Eslaminejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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18
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Bondos SE, Geraldo Mendes G, Jons A. Context-dependent HOX transcription factor function in health and disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 174:225-262. [PMID: 32828467 DOI: 10.1016/bs.pmbts.2020.05.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
During animal development, HOX transcription factors determine the fate of developing tissues to generate diverse organs and appendages. The power of these proteins is striking: mis-expressing a HOX protein causes homeotic transformation of one body part into another. During development, HOX proteins interpret their cellular context through protein interactions, alternative splicing, and post-translational modifications to regulate cell proliferation, cell death, cell migration, cell differentiation, and angiogenesis. Although mutation and/or mis-expression of HOX proteins during development can be lethal, changes in HOX proteins that do not pattern vital organs can result in survivable malformations. In adults, mutation and/or mis-expression of HOX proteins disrupts their gene regulatory networks, deregulating cell behaviors and leading to arthritis and cancer. On the molecular level, HOX proteins are composed of DNA binding homeodomain, and large regions of unstructured, or intrinsically disordered, protein sequence. The primary roles of HOX proteins in arthritis and cancer suggest that mutations associated with these diseases in both the structured and disordered regions of HOX proteins can have substantial functional effects. These insights lead to new questions critical for understanding and manipulating HOX function in physiological and pathological conditions.
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Affiliation(s)
- Sarah E Bondos
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, United States.
| | - Gabriela Geraldo Mendes
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, United States
| | - Amanda Jons
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, United States
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19
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Liu N, Zhang Z, Li L, Shen X, Sun B, Wang R, Zhong H, Shi Q, Wei L, Zhang Y, Wang Y, Xu C, Liu Y, Yuan W. MicroRNA-181 regulates the development of Ossification of Posterior longitudinal ligament via Epigenetic Modulation by targeting PBX1. Theranostics 2020; 10:7492-7509. [PMID: 32685001 PMCID: PMC7359103 DOI: 10.7150/thno.44309] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 06/02/2020] [Indexed: 12/24/2022] Open
Abstract
Objectives: Ossification of the posterior longitudinal ligament (OPLL) presents as the development of heterotopic ossification in the posterior longitudinal ligament of the spine. The etiology of OPLL is genetically linked, as shown by its high prevalence in Asian populations. However, the molecular mechanism of the disease remains obscure. In this study, we explored the function and mechanism of OPLL-specific microRNAs. Methods: The expression levels of the ossification-related OPLL-specific miR-181 family were measured in normal or OPLL ligament tissues. The effect of miR-181a on the ossification of normal or pathogenic ligament cells was tested using real-time polymerase chain reaction (PCR), Western blot, alizarin red staining and alkaline phosphatase (ALP) staining. The candidate targets of miR-181 were screened using a dual luciferase reporter assay and functional analysis. The link between miR-181a and its target PBX1 was investigated using chromatin immunoprecipitation, followed by real-time PCR detection. Histological and immunohistochemical analysis as well as micro-CT scanning were used to evaluate the effects of miR-181 and its antagonist using both tip-toe-walking OPLL mice and in vivo bone formation assays. Results: Using bioinformatic analysis, we found that miR-181a-5p is predicted to play important roles in the development of OPLL. Overexpression of miR-181a-5p significantly increased the expression of ossification-related genes, staining level of alizarin red and ALP activity, while the inhibition of miR-181a-5p by treatment with an antagomir had the opposite effects. Functional analysis identified PBX1 as a direct target of miR-181a-5p, and we determined that PBX1 was responsible for miR-181a-5p's osteogenic phenotype. By chromatin immunoprecipitation assay, we found that miR-181a-5p controls ligament cell ossification by regulating PBX1-mediated modulation of histone methylation and acetylation levels in the promoter region of osteogenesis-related genes. Additionally, using an in vivo model, we confirmed that miR-181a-5p can substantially increase the bone formation ability of posterior ligament cells and cause increased osteophyte formation in the cervical spine of tip-toe-walking mice. Conclusions: Our data unveiled the mechanism by which the miR-181a-5p/PBX1 axis functions in the development of OPLL, and it revealed the therapeutic effects of the miR-181a-5p antagomir in preventing OPLL development both in vivo and in vitro. Our work is the first to demonstrate that microRNA perturbation could modulate the development of OPLL through epigenetic regulation.
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Affiliation(s)
- Ning Liu
- Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, PR China
| | - Zicheng Zhang
- Undergraduate Brigade, Changhai Hospital Affiliated to Second Military Medical University, 168th Chang Hai Road, Shanghai, 200433, China
| | - Li Li
- Research Center of Developmental Biology, Second Military Medical University, 800th Xiang Yin Road, Shanghai, 200433, PR China
| | - Xiaolong Shen
- Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, PR China
| | - Baifeng Sun
- Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, PR China
| | - Ruizhe Wang
- Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, PR China
| | - Huajian Zhong
- Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, PR China
| | - Qianghui Shi
- Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, PR China
| | - Leixin Wei
- Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, PR China
| | - Yizhi Zhang
- Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, PR China
| | - Yue Wang
- Research Center of Developmental Biology, Second Military Medical University, 800th Xiang Yin Road, Shanghai, 200433, PR China
| | - Chen Xu
- Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, PR China
| | - Yang Liu
- Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, PR China
| | - Wen Yuan
- Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003, PR China
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20
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Wang K, Wang Y, Hu Z, Zhang L, Li G, Dang L, Tan Y, Cao X, Shi F, Zhang S, Zhang G. Bone-targeted lncRNA OGRU alleviates unloading-induced bone loss via miR-320-3p/Hoxa10 axis. Cell Death Dis 2020; 11:382. [PMID: 32427900 PMCID: PMC7237470 DOI: 10.1038/s41419-020-2574-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/28/2020] [Accepted: 04/28/2020] [Indexed: 01/13/2023]
Abstract
Unloading-induced bone loss is a threat to human health and can eventually result in osteoporotic fractures. Although the underlying molecular mechanism of unloading-induced bone loss has been broadly elucidated, the pathophysiological role of long noncoding RNAs (lncRNAs) in this process is unknown. Here, we identified a novel lncRNA, OGRU, a 1816-nucleotide transcript with significantly decreased levels in bone specimens from hindlimb-unloaded mice and in MC3T3-E1 cells under clinorotation-unloading conditions. OGRU overexpression promoted osteoblast activity and matrix mineralization under normal loading conditions, and attenuated the suppression of MC3T3-E1 cell differentiation induced by clinorotation unloading. Furthermore, this study found that supplementation of pcDNA3.1(+)–OGRU via (DSS)6–liposome delivery to the bone-formation surfaces of hindlimb-unloaded (HLU) mice partially alleviated unloading-induced bone loss. Mechanistic investigations demonstrated that OGRU functions as a competing endogenous RNA (ceRNA) to facilitate the protein expression of Hoxa10 by competitively binding miR-320-3p and subsequently promote osteoblast differentiation and bone formation. Taken together, the results of our study provide the first clarification of the role of lncRNA OGRU in unloading-induced bone loss through the miR-320-3p/Hoxa10 axis, suggesting an efficient anabolic strategy for osteoporosis treatment.
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Affiliation(s)
- Ke Wang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Yixuan Wang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Zebing Hu
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Lijun Zhang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Gaozhi Li
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Lei Dang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Yingjun Tan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China
| | - Xinsheng Cao
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Fei Shi
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China.
| | - Shu Zhang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China.
| | - Ge Zhang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
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21
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Wikenius E, Moe V, Smith L, Heiervang ER, Berglund A. DNA methylation changes in infants between 6 and 52 weeks. Sci Rep 2019; 9:17587. [PMID: 31772264 PMCID: PMC6879561 DOI: 10.1038/s41598-019-54355-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 11/14/2019] [Indexed: 12/16/2022] Open
Abstract
Infants undergo extensive developments during their first year of life. Although the biological mechanisms involved are not yet fully understood, changes in the DNA methylation in mammals are believed to play a key role. This study was designed to investigate changes in infant DNA methylation that occurs between 6 and 52 weeks. A total of 214 infant saliva samples from 6 or 52 weeks were assessed using principal component analyses and t-distributed stochastic neighbor-embedding algorithms. Between the two time points, there were clear differences in DNA methylation. To further investigate these findings, paired two-sided student’s t-tests were performed. Differently methylated regions were defined as at least two consecutive probes that showed significant differences, with a q-value < 0.01 and a mean difference > 0.2. After correcting for false discovery rates, changes in the DNA methylation levels were found in 42 genes. Of these, 36 genes showed increased and six decreased DNA methylation. The overall DNA methylation changes indicated decreased gene expression. This was surprising because infants undergo such profound developments during their first year of life. The results were evaluated by taking into consideration the extensive development that occurs during pregnancy. During the first year of life, infants have an overall three-fold increase in weight, while the fetus develops from a single cell into a viable infant in 9 months, with an 875-million-fold increase in weight. It is possible that the findings represent a biological slowing mechanism in response to extensive fetal development. In conclusion, our study provides evidence of DNA methylation changes during the first year of life, representing a possible biological slowing mechanism. We encourage future studies of DNA methylation changes in infants to replicate the findings by using a repeated measures model and less stringent criteria to see if the same genes can be found, as well as investigating whether other genes are involved in development during this period.
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Affiliation(s)
- Ellen Wikenius
- H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Vibeke Moe
- Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway.,The Center for Child and Adolescent Mental Health, Eastern and Southern Norway (RBUP), Oslo, Norway
| | - Lars Smith
- Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway
| | - Einar R Heiervang
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Oslo University Hospital, Oslo, Norway
| | - Anders Berglund
- H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
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22
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Cardenas A, Lutz SM, Everson TM, Perron P, Bouchard L, Hivert MF. Mediation by Placental DNA Methylation of the Association of Prenatal Maternal Smoking and Birth Weight. Am J Epidemiol 2019; 188:1878-1886. [PMID: 31497855 DOI: 10.1093/aje/kwz184] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 04/17/2019] [Accepted: 04/22/2019] [Indexed: 02/06/2023] Open
Abstract
Prenatal maternal smoking is a risk factor for lower birth weight. We performed epigenome-wide association analyses of placental DNA methylation (DNAm) at 720,077 cytosine-phosphate-guanine (CpG) sites and prenatal maternal smoking among 441 mother-infant pairs (2010-2014) and evaluated whether DNAm mediates the association between smoking and birth weight using mediation analysis. Mean birth weight was 3,443 (standard deviation, 423) g, and 38 mothers (8.6%) reported smoking at a mean of 9.4 weeks of gestation. Prenatal maternal smoking was associated with a 175-g lower birth weight (95% confidence interval (CI): -305.5, -44.8) and with differential DNAm of 71 CpGs in placenta, robust to latent-factor adjustment reflecting cell types (Bonferroni-adjusted P < 6.94 × 10-8). Of the 71 CpG sites, 7 mediated the association between prenatal smoking and birth weight (on MDS2, PBX1, CYP1A2, VPRBP, WBP1L, CD28, and CDK6 genes), and prenatal smoking × DNAm interactions on birth weight were observed for 5 CpG sites. The strongest mediator, cg22638236, was annotated to the PBX1 gene body involved in skeletal patterning and programming, with a mediated effect of 301-g lower birth weight (95% CI: -543, -86) among smokers but no mediated effect for nonsmokers (β = -38 g; 95% CI: -88, 9). Prenatal maternal smoking might interact with placental DNAm at specific loci, mediating the association with lower infant birth weight.
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23
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Gu J, Lu Y, Deng M, Qiu M, Tian Y, Ji Y, Zong P, Shao Y, Zheng R, Zhou B, Sun W, Kong X. Inhibition of acetylation of histones 3 and 4 attenuates aortic valve calcification. Exp Mol Med 2019; 51:1-14. [PMID: 31292436 PMCID: PMC6802657 DOI: 10.1038/s12276-019-0272-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 02/04/2019] [Accepted: 03/06/2019] [Indexed: 02/08/2023] Open
Abstract
Aortic valve calcification develops in patients with chronic kidney disease who have calcium and phosphate metabolic disorders and poor prognoses. There is no effective treatment except valve replacement. However, metabolic disorders put patients at high risk for surgery. Increased acetylation of histones 3 and 4 is present in interstitial cells from human calcific aortic valves, but whether it is involved in aortic valve calcification has not been studied. In this study, we found that treating cultured porcine aortic valve interstitial cells with a high-calcium/high-phosphate medium induced calcium deposition, apoptosis, and expression of osteogenic marker genes, producing a phenotype resembling valve calcification in vivo. These phenotypic changes were attenuated by the histone acetyltransferase inhibitor C646. C646 treatment increased the levels of class I histone deacetylase members and decreased the acetylation of histones 3 and 4 induced by the high-calcium/high-phosphate treatment. Conversely, the histone deacetylase inhibitor suberoylanilide hydroxamic acid promoted valve interstitial cell calcification. In a mouse model of aortic valve calcification induced by adenine and vitamin D treatment, the levels of acetylated histones 3 and 4 were increased in the calcified aortic valves. Treatment of the models with C646 attenuated aortic valve calcification by restoring the levels of acetylated histones 3 and 4. These observations suggest that increased acetylation of histones 3 and 4 is part of the pathogenesis of aortic valve calcification associated with calcium and phosphate metabolic disorders. Targeting acetylated histones 3 and 4 may be a potential therapy for inoperable aortic valve calcification in chronic kidney disease patients.
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Affiliation(s)
- Jia Gu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, PR China
| | - Yan Lu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, PR China
| | - Menqing Deng
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, PR China
| | - Ming Qiu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, PR China
| | - Yunfan Tian
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, PR China
| | - Yue Ji
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, PR China
| | - Pengyu Zong
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, PR China
| | - Yongfeng Shao
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, PR China
| | - Rui Zheng
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, PR China
| | - Bin Zhou
- Departments of Genetics, Pediatrics, and Medicine (Cardiology), The Wilf Cardiovascular Research Institute, The Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Wei Sun
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, PR China.
| | - Xiangqing Kong
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, PR China.
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Bone Remodeling: Histone Modifications as Fate Determinants of Bone Cell Differentiation. Int J Mol Sci 2019; 20:ijms20133147. [PMID: 31252653 PMCID: PMC6651527 DOI: 10.3390/ijms20133147] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 06/21/2019] [Accepted: 06/24/2019] [Indexed: 02/07/2023] Open
Abstract
The bone tissue is a dynamic complex that constitutes of several interdependent systems and is continuously remodeled through the concerted actions of bone cells. Osteoblasts are mononucleated cells, derived from mesenchymal stem cells, responsible for bone formation. Osteoclasts are large multinucleated cells that differentiate from hematopoietic progenitors of the myeloid lineage and are responsible for bone resorption. The lineage-specific differentiation of bone cells requires an epigenetic regulation of gene expressions involving chromatin dynamics. The key step for understanding gene regulatory networks during bone cell development lies in characterizing the chromatin modifying enzymes responsible for reorganizing and potentiating particular chromatin structure. This review covers the histone-modifying enzymes involved in bone development, discusses the impact of enzymes on gene expression, and provides future directions and clinical significance in this area.
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25
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Welsh IC, Hart J, Brown JM, Hansen K, Rocha Marques M, Aho RJ, Grishina I, Hurtado R, Herzlinger D, Ferretti E, Garcia-Garcia MJ, Selleri L. Pbx loss in cranial neural crest, unlike in epithelium, results in cleft palate only and a broader midface. J Anat 2018; 233:222-242. [PMID: 29797482 PMCID: PMC6036936 DOI: 10.1111/joa.12821] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2018] [Indexed: 01/21/2023] Open
Abstract
Orofacial clefting represents the most common craniofacial birth defect. Cleft lip with or without cleft palate (CL/P) is genetically distinct from cleft palate only (CPO). Numerous transcription factors (TFs) regulate normal development of the midface, comprising the premaxilla, maxilla and palatine bones, through control of basic cellular behaviors. Within the Pbx family of genes encoding Three Amino-acid Loop Extension (TALE) homeodomain-containing TFs, we previously established that in the mouse, Pbx1 plays a preeminent role in midfacial morphogenesis, and Pbx2 and Pbx3 execute collaborative functions in domains of coexpression. We also reported that Pbx1 loss from cephalic epithelial domains, on a Pbx2- or Pbx3-deficient background, results in CL/P via disruption of a regulatory network that controls apoptosis at the seam of frontonasal and maxillary process fusion. Conversely, Pbx1 loss in cranial neural crest cell (CNCC)-derived mesenchyme on a Pbx2-deficient background results in CPO, a phenotype not yet characterized. In this study, we provide in-depth analysis of PBX1 and PBX2 protein localization from early stages of midfacial morphogenesis throughout development of the secondary palate. We further establish CNCC-specific roles of PBX TFs and describe the developmental abnormalities resulting from their loss in the murine embryonic secondary palate. Additionally, we compare and contrast the phenotypes arising from PBX1 loss in CNCC with those caused by its loss in the epithelium and show that CNCC-specific Pbx1 deletion affects only later secondary palate morphogenesis. Moreover, CNCC mutants exhibit perturbed rostro-caudal organization and broadening of the midfacial complex. Proliferation defects are pronounced in CNCC mutants at gestational day (E)12.5, suggesting altered proliferation of mutant palatal progenitor cells, consistent with roles of PBX factors in maintaining progenitor cell state. Although the craniofacial skeletal abnormalities in CNCC mutants do not result from overt patterning defects, osteogenesis is delayed, underscoring a critical role of PBX factors in CNCC morphogenesis and differentiation. Overall, the characterization of tissue-specific Pbx loss-of-function mouse models with orofacial clefting establishes these strains as unique tools to further dissect the complexities of this congenital craniofacial malformation. This study closely links PBX TALE homeodomain proteins to the variation in maxillary shape and size that occurs in pathological settings and during evolution of midfacial morphology.
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Affiliation(s)
- Ian C Welsh
- Program in Craniofacial Biology, Departments of Orofacial Sciences and Anatomy, Institute of Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - James Hart
- Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Joel M Brown
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Karissa Hansen
- Program in Craniofacial Biology, Departments of Orofacial Sciences and Anatomy, Institute of Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Marcelo Rocha Marques
- Program in Craniofacial Biology, Departments of Orofacial Sciences and Anatomy, Institute of Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Robert J Aho
- Program in Craniofacial Biology, Departments of Orofacial Sciences and Anatomy, Institute of Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Irina Grishina
- Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Romulo Hurtado
- Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Doris Herzlinger
- Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | - Elisabetta Ferretti
- Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | | | - Licia Selleri
- Program in Craniofacial Biology, Departments of Orofacial Sciences and Anatomy, Institute of Human Genetics, University of California San Francisco, San Francisco, CA, USA
- Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, New York, NY, USA
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26
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He C, Wang Z, Zhang L, Yang L, Li J, Chen X, Zhang J, Chang Q, Yu Y, Liu B, Zhu Z. A hydrophobic residue in the TALE homeodomain of PBX1 promotes epithelial-to-mesenchymal transition of gastric carcinoma. Oncotarget 2018; 8:46818-46833. [PMID: 28514754 PMCID: PMC5564525 DOI: 10.18632/oncotarget.17473] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 04/12/2017] [Indexed: 01/24/2023] Open
Abstract
Pre-B-cell leukemia homeobox 1 (PBX1) was originally identified as a proto-oncogene in human leukemia. Although this protein has been shown to contribute to cellular development and tumorigenesis, the role of PBX1 in gastric carcinoma (GC) remains unclear. In this study, we observed increased expression of PBX1 in GC tissues compared with adjacent normal tissues. This increase in PBX1 expression levels negatively correlated with HOXB9 mRNA expression and was also associated with malignancy and metastasis. PBX1 promoted proliferation and metastasis of GC cells both in vitro and in vivo. These phenomena were also accompanied by epithelial-to-mesenchymal transition (EMT). Additionally, we observed that PBX1 promotes the expression of tumor growth and angiogenic factors. A structural model of the PBX1-HOX complex revealed that hydrophobic binding between PBX1 and the hexapeptide motif might be required for EMT induction. This analysis also demonstrated that the Phe252 residue in the first helix of the TALE homeodomain is involved in the latter hydrophobic binding reaction. In vitro data from PBX1 mutants suggest that PBX1 cannot promote tumorigenesis of GC cells via EMT induction when Phe252 residues lose hydrophobicity. It is likely that the presence of this residue is essential in facilitating hydrophobic binding with the hexapeptide motif. These findings suggest that PBX1 may be a potential target for GC treatment and this study provides a platform to elucidate the molecular mechanisms that underpin the role of PBX1 in GC tumorigenesis.
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Affiliation(s)
- Changyu He
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenqiang Wang
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Zhang
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liyun Yang
- Department of Otolaryngology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianfang Li
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuehua Chen
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Zhang
- Department of Clinical Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Chang
- Clinical Research Center, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Yingyan Yu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenggang Zhu
- Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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27
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Sepulveda H, Villagra A, Montecino M. Tet-Mediated DNA Demethylation Is Required for SWI/SNF-Dependent Chromatin Remodeling and Histone-Modifying Activities That Trigger Expression of the Sp7 Osteoblast Master Gene during Mesenchymal Lineage Commitment. Mol Cell Biol 2017; 37:e00177-17. [PMID: 28784721 PMCID: PMC5615189 DOI: 10.1128/mcb.00177-17] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 05/15/2017] [Accepted: 07/22/2017] [Indexed: 12/22/2022] Open
Abstract
Here we assess histone modification, chromatin remodeling, and DNA methylation processes that coordinately control the expression of the bone master transcription factor Sp7 (osterix) during mesenchymal lineage commitment in mammalian cells. We find that Sp7 gene silencing is mediated by DNA methyltransferase1/3 (DNMT1/3)-, histone deacetylase 1/2/4 (HDAC1/2/4)-, Setdb1/Suv39h1-, and Ezh1/2-containing complexes. In contrast, Sp7 gene activation involves changes in histone modifications, accompanied by decreased nucleosome enrichment and DNA demethylation mediated by SWI/SNF- and Tet1/Tet2-containing complexes, respectively. Inhibition of DNA methylation triggers changes in the histone modification profile and chromatin-remodeling events leading to Sp7 gene expression. Tet1/Tet2 silencing prevents Sp7 expression during osteoblast differentiation as it impairs DNA demethylation and alters the recruitment of histone methylase (COMPASS)-, histone demethylase (Jmjd2a/Jmjd3)-, and SWI/SNF-containing complexes to the Sp7 promoter. The dissection of these interconnected epigenetic mechanisms that govern Sp7 gene activation reveals a hierarchical process where regulatory components mediating DNA demethylation play a leading role.
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Affiliation(s)
- Hugo Sepulveda
- Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile
- FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile
| | - Alejandro Villagra
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA
| | - Martin Montecino
- Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile
- FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile
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28
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Bianchi MV, Awaja F, Altankov G. Dynamic adhesive environment alters the differentiation potential of young and ageing mesenchymal stem cells. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2017; 78:467-474. [DOI: 10.1016/j.msec.2017.04.110] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 04/18/2017] [Accepted: 04/19/2017] [Indexed: 11/27/2022]
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29
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Grebbin BM, Schulte D. PBX1 as Pioneer Factor: A Case Still Open. Front Cell Dev Biol 2017; 5:9. [PMID: 28261581 PMCID: PMC5306212 DOI: 10.3389/fcell.2017.00009] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 01/31/2017] [Indexed: 12/19/2022] Open
Abstract
Pioneer factors are proteins that can recognize their target sites in barely accessible chromatin and initiate a cascade of events that allows for later transcriptional activation of the respective genes. Pioneer factors are therefore particularly well-suited to initiate cell fate changes. To date, only a small number of pioneer factors have been identified and studied in depth, such as FOXD3/FOXA1, OCT4, or SOX2. Interestingly, several recent studies reported that the PBC transcription factor PBX1 can access transcriptionally inactive genomic loci. Here, we summarize the evidence linking PBX1 with transcriptional pioneer functions, suggest potential mechanisms involved and discuss open questions to be resolved.
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Affiliation(s)
- Britta M Grebbin
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, J. W. Goethe University Frankfurt, Germany
| | - Dorothea Schulte
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, J. W. Goethe University Frankfurt, Germany
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30
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Agha G, Hajj H, Rifas-Shiman SL, Just AC, Hivert MF, Burris HH, Lin X, Litonjua AA, Oken E, DeMeo DL, Gillman MW, Baccarelli AA. Birth weight-for-gestational age is associated with DNA methylation at birth and in childhood. Clin Epigenetics 2016; 8:118. [PMID: 27891191 PMCID: PMC5112715 DOI: 10.1186/s13148-016-0285-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 11/02/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Both higher and lower fetal growth are associated with cardio-metabolic health later in life, suggesting that prenatal developmental programming determines long-term cardiovascular disease risk. Epigenetic mechanisms, which orchestrate fetal growth and development, may offer insight on the early programming of health and disease. We investigated whether birth weight-for-gestational is associated with DNA methylation at birth and mid-childhood, measured via the Infinium 450K array. METHODS/RESULTS Participants were from Project Viva, a pre-birth cohort of pregnant women and their children in Eastern Massachusetts. After exclusion of participants with maternal type 1 or 2 diabetes and gestational age <34 weeks, we used DNA methylation assays from 476 venous umbilical cord blood samples and a subset of 235 who additionally had peripheral blood samples available in mid-childhood (age 7-10 years). Among 392,918 CpG sites analyzed, birth weight-for-gestational age z-score was associated with cord blood DNA methylation at 34 CpGs (false discovery rate P < 0.05), after adjusting for maternal age, race/ethnicity, education, smoking, parity, delivery mode, pre-pregnancy BMI, gestational diabetes status, child sex, and estimated cord blood cell proportions based on a cord blood reference panel. Two of these CpGs were previously reported in epigenome-wide analyses of birth weight, and several other CpGs map to genes relevant to fetal growth and development. Namely, higher birth weight-for-gestational age was associated with higher methylation at four CpGs at the PBX1 locus (e.g., β (95% CI) for lead signal at cg06750897 = 1.9 (1.2, 2.6)), which encodes a transcription factor that regulates embryonic development. Birth weight-for-gestational age was also associated with mid-childhood blood DNA methylation at four of the 34 CpGs identified in cord blood analyses, including sites at the PBX1 locus described. CONCLUSIONS We identified CpG sites where birth weight-for-gestational age was associated with DNA methylation at birth, and for a subset of these sites, birth weight-for-gestational age was also associated with DNA methylation at mid-childhood.
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Affiliation(s)
- Golareh Agha
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY 10032 USA
| | - Hanine Hajj
- Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA USA
| | - Sheryl L. Rifas-Shiman
- Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA USA
| | - Allan C. Just
- Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Marie-France Hivert
- Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA USA
| | - Heather H. Burris
- Department of Neonatology, Beth Israel Deaconess Medical Center, Department of Pediatrics, Harvard Medical School, Boston, MA USA
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA USA
| | - Xihong Lin
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA USA
| | | | - Emily Oken
- Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA USA
| | - Dawn L. DeMeo
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
| | - Matthew W. Gillman
- Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA USA
| | - Andrea A. Baccarelli
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY 10032 USA
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31
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Liu Y, Zhang XL, Chen L, Lin X, Xiong D, Xu F, Yuan LQ, Liao EY. Epigenetic mechanisms of bone regeneration and homeostasis. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2016; 122:85-92. [DOI: 10.1016/j.pbiomolbio.2016.01.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 12/24/2015] [Accepted: 01/06/2016] [Indexed: 01/08/2023]
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32
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Li Y, Buckhaults P, Cui X, Tollefsbol TO. Combinatorial epigenetic mechanisms and efficacy of early breast cancer inhibition by nutritive botanicals. Epigenomics 2016; 8:1019-37. [PMID: 27478970 PMCID: PMC5066124 DOI: 10.2217/epi-2016-0024] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Aim: Aberrant epigenetic events are important contributors to the pathogenesis of different types of cancers and dietary botanicals with epigenetic properties can influence early cancer development leading to cancer prevention effects. We sought to investigate potential combinatorial effects of bioactive dietary components including green tea polyphenols (GTPs) and broccoli sprouts (BSp) on neutralizing epigenetic aberrations during breast tumorigenesis. Materials & methods: The combinatorial effects were evaluated in a breast cancer transformation cellular system and breast cancer mouse xenografts. Results & conclusion: Combined treatment with epigallocatechin-3-gallate in GTPs and sulforaphane in BSp resulted in a synergistic inhibition of breast cancer cellular growth. Further studies revealed this combination led to genome-wide epigenetic alterations. Combinatorial diets significantly inhibited tumor growth in breast cancer mouse xenografts. Collectively, these studies indicate that combined GTPs and BSp are highly effective in inhibiting early breast cancer development by, at least in part, regulating epigenetic mechanisms.
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Affiliation(s)
- Yuanyuan Li
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Phillip Buckhaults
- Department of Drug Discovery & Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Xiangqin Cui
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Trygve O Tollefsbol
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.,Comprehensive Center for Healthy Aging, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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33
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Grebbin BM, Hau AC, Groß A, Anders-Maurer M, Schramm J, Koss M, Wille C, Mittelbronn M, Selleri L, Schulte D. Pbx1 is required for adult subventricular zone neurogenesis. Development 2016; 143:2281-91. [PMID: 27226325 DOI: 10.1242/dev.128033] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 05/15/2016] [Indexed: 12/22/2022]
Abstract
TALE-homeodomain proteins function as components of heteromeric complexes that contain one member each of the PBC and MEIS/PREP subclasses. We recently showed that MEIS2 cooperates with the neurogenic transcription factor PAX6 in the control of adult subventricular zone (SVZ) neurogenesis in rodents. Expression of the PBC protein PBX1 in the SVZ has been reported, but its functional role(s) has not been investigated. Using a genetic loss-of-function mouse model, we now show that Pbx1 is an early regulator of SVZ neurogenesis. Targeted deletion of Pbx1 by retroviral transduction of Cre recombinase into Pbx2-deficient SVZ stem and progenitor cells carrying floxed alleles of Pbx1 significantly reduced the production of neurons and increased the generation of oligodendrocytes. Loss of Pbx1 expression in neuronally committed neuroblasts in the rostral migratory stream in a Pbx2 null background, by contrast, severely compromised cell survival. By chromatin immunoprecipitation from endogenous tissues or isolated cells, we further detected PBX1 binding to known regulatory regions of the neuron-specific genes Dcx and Th days or even weeks before the respective genes are expressed during the normal program of SVZ neurogenesis, suggesting that PBX1 might act as a priming factor to mark these genes for subsequent activation. Collectively, our results establish that PBX1 regulates adult neural cell fate determination in a manner beyond that of its heterodimerization partner MEIS2.
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Affiliation(s)
- Britta Moyo Grebbin
- Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany
| | - Ann-Christin Hau
- Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany
| | - Anja Groß
- Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany
| | - Marie Anders-Maurer
- Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany
| | - Jasmine Schramm
- Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany
| | - Matthew Koss
- Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
| | - Christoph Wille
- Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany
| | - Michel Mittelbronn
- Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany
| | - Licia Selleri
- Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA Program in Craniofacial Biology, Institute of Human Genetics, Eli and Edythe Broad Center of Regeneration Medicine & Stem Cell Research, Departments of Orofacial Sciences and Anatomy, University of California, San Francisco, 513 Parnassus Avenue, HSW 710, San Francisco, CA 94143, USA
| | - Dorothea Schulte
- Institute of Neurology (Edinger Institute), J. W. Goethe University Medical School, German Cancer Consortium (DKTK), Heinrich-Hoffmann Str. 7, Frankfurt D-60528, Germany
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Abstract
Metazoans encode clusters of paralogous Hox genes that are critical for proper development of the body plan. However, there are a number of unresolved issues regarding how paralogous Hox factors achieve specificity to control distinct cell fates. First, how do Hox paralogs, which have very similar DNA binding preferences in vitro, drive different transcriptional programs in vivo? Second, the number of potential Hox binding sites within the genome is vast compared to the number of sites bound. Hence, what determines where in the genome Hox factors bind? Third, what determines whether a Hox factor will activate or repress a specific target gene? Here, we review the current evidence that is beginning to shed light onto these questions. In particular, we highlight how cooperative interactions with other transcription factors (especially PBC and HMP proteins) and the sequences of cis-regulatory modules provide a basis for the mechanisms of Hox specificity. We conclude by integrating a number of the concepts described throughout the review in a case study of a highly interrogated Drosophila cis-regulatory module named “The Distal-less Conserved Regulatory Element” (DCRE).
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Affiliation(s)
- Arya Zandvakili
- Molecular and Developmental Biology Graduate Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Medical-Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA;
| | - Brian Gebelein
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Correspondence: ; Tel.: +1-513-636-3366
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Rezsohazy R, Saurin AJ, Maurel-Zaffran C, Graba Y. Cellular and molecular insights into Hox protein action. Development 2016; 142:1212-27. [PMID: 25804734 DOI: 10.1242/dev.109785] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hox genes encode homeodomain transcription factors that control morphogenesis and have established functions in development and evolution. Hox proteins have remained enigmatic with regard to the molecular mechanisms that endow them with specific and diverse functions, and to the cellular functions that they control. Here, we review recent examples of Hox-controlled cellular functions that highlight their versatile and highly context-dependent activity. This provides the setting to discuss how Hox proteins control morphogenesis and organogenesis. We then summarise the molecular modalities underlying Hox protein function, in particular in light of current models of transcription factor function. Finally, we discuss how functional divergence between Hox proteins might be achieved to give rise to the many facets of their action.
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Affiliation(s)
- René Rezsohazy
- Institut des Sciences de la Vie, Université Catholique de Louvain, Louvain-la-Neuve B-1348, Belgium
| | - Andrew J Saurin
- Aix Marseille Université, CNRS, IBDM, UMR 7288, Marseille 13288, Cedex 09, France
| | | | - Yacine Graba
- Aix Marseille Université, CNRS, IBDM, UMR 7288, Marseille 13288, Cedex 09, France
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36
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Gordon JAR, Stein JL, Westendorf JJ, van Wijnen AJ. Chromatin modifiers and histone modifications in bone formation, regeneration, and therapeutic intervention for bone-related disease. Bone 2015; 81:739-745. [PMID: 25836763 PMCID: PMC4591092 DOI: 10.1016/j.bone.2015.03.011] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 03/13/2015] [Indexed: 02/07/2023]
Abstract
Post-translational modifications of chromatin such as DNA methylation and different types of histone acetylation, methylation and phosphorylation are well-appreciated epigenetic mechanisms that confer information to progeny cells during lineage commitment. These distinct epigenetic modifications have defined roles in bone, development, tissue regeneration, cell commitment and differentiation, as well as disease etiologies. In this review, we discuss the role of these chromatin modifications and the enzymes regulating these marks (methyltransferases, demethylases, acetyltransferases, and deacetylases) in progenitor cells, osteoblasts and bone-related cells. In addition, the clinical relevance of deregulated histone modifications and enzymes as well as current and potential therapeutic interventions targeting chromatin modifiers are addressed.
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Affiliation(s)
| | - Janet L Stein
- Department of Biochemistry, University of Vermont, Burlington, VT, USA.
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Seifert A, Werheid DF, Knapp SM, Tobiasch E. Role of Hox genes in stem cell differentiation. World J Stem Cells 2015; 7:583-595. [PMID: 25914765 PMCID: PMC4404393 DOI: 10.4252/wjsc.v7.i3.583] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 11/20/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
Hox genes are an evolutionary highly conserved gene family. They determine the anterior-posterior body axis in bilateral organisms and influence the developmental fate of cells. Embryonic stem cells are usually devoid of any Hox gene expression, but these transcription factors are activated in varying spatial and temporal patterns defining the development of various body regions. In the adult body, Hox genes are among others responsible for driving the differentiation of tissue stem cells towards their respective lineages in order to repair and maintain the correct function of tissues and organs. Due to their involvement in the embryonic and adult body, they have been suggested to be useable for improving stem cell differentiations in vitro and in vivo. In many studies Hox genes have been found as driving factors in stem cell differentiation towards adipogenesis, in lineages involved in bone and joint formation, mainly chondrogenesis and osteogenesis, in cardiovascular lineages including endothelial and smooth muscle cell differentiations, and in neurogenesis. As life expectancy is rising, the demand for tissue reconstruction continues to increase. Stem cells have become an increasingly popular choice for creating therapies in regenerative medicine due to their self-renewal and differentiation potential. Especially mesenchymal stem cells are used more and more frequently due to their easy handling and accessibility, combined with a low tumorgenicity and little ethical concerns. This review therefore intends to summarize to date known correlations between natural Hox gene expression patterns in body tissues and during the differentiation of various stem cells towards their respective lineages with a major focus on mesenchymal stem cell differentiations. This overview shall help to understand the complex interactions of Hox genes and differentiation processes all over the body as well as in vitro for further improvement of stem cell treatments in future regenerative medicine approaches.
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Meyer MB, Benkusky NA, Pike JW. The RUNX2 cistrome in osteoblasts: characterization, down-regulation following differentiation, and relationship to gene expression. J Biol Chem 2014; 289:16016-31. [PMID: 24764292 PMCID: PMC4047377 DOI: 10.1074/jbc.m114.552216] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 04/23/2014] [Indexed: 01/09/2023] Open
Abstract
RUNX2 is a transcription factor that is first expressed in early osteoblast-lineage cells and represents a primary determinant of osteoblastogenesis. While numerous target genes are regulated by RUNX2, little is known of sites on the genome occupied by RUNX2 or of the gene networks that are controlled by these sites. To explore this, we conducted a genome-wide analysis of the RUNX2 cistrome in both pre-osteoblastic MC3T3-E1 cells (POB) and their mature osteoblast progeny (OB), characterized the two cistromes and assessed their relationship to changes in gene expression. We found that although RUNX2 was widely bound to the genome in POB cells, this binding profile was reduced upon differentiation to OBs. Numerous sites were lost upon differentiation, new sites were also gained; many sites remained common to both cell states. Additional features were identified as well including location relative to potential target genes, abundance with respect to single genes, the frequent presence of a consensus TGTGGT RUNX2 binding motif, co-occupancy by C/EBPβ and the presence of a typical epigenetic histone enhancer signature. This signature was changed quantitatively following differentiation. While RUNX2 binding sites were associated extensively with adjacent genes, the distal nature of the majority of these sites prevented assessment of whether they represented direct targets of RUNX2 action. Changes in gene expression, however, revealed an abundance of genes that contained RUNX2 binding sites and were regulated in concert. These studies establish a basis for further analysis of the role of RUNX2 activity and its function during osteoblast lineage maturation.
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Affiliation(s)
- Mark B Meyer
- From the Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706
| | - Nancy A Benkusky
- From the Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706
| | - J Wesley Pike
- From the Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706
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Delgado-Calle J, Fernández AF, Sainz J, Zarrabeitia MT, Sañudo C, García-Renedo R, Pérez-Núñez MI, García-Ibarbia C, Fraga MF, Riancho JA. Genome-wide profiling of bone reveals differentially methylated regions in osteoporosis and osteoarthritis. ACTA ACUST UNITED AC 2012; 65:197-205. [DOI: 10.1002/art.37753] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2012] [Accepted: 10/09/2012] [Indexed: 12/20/2022]
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40
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Ciciarello M, Zini R, Rossi L, Salvestrini V, Ferrari D, Manfredini R, Lemoli RM. Extracellular purines promote the differentiation of human bone marrow-derived mesenchymal stem cells to the osteogenic and adipogenic lineages. Stem Cells Dev 2012; 22:1097-111. [PMID: 23259837 DOI: 10.1089/scd.2012.0432] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Extracellular nucleotides are potent signaling molecules mediating cell-specific biological functions, mostly within the processes of tissue damage and repair and flogosis. We previously demonstrated that adenosine 5'-triphosphate (ATP) inhibits the proliferation of human bone marrow-derived mesenchymal stem cells (BM-hMSCs), while stimulating, in vitro and in vivo, their migration. Here, we investigated the effects of ATP on BM-hMSC differentiation capacity. Molecular analysis showed that ATP treatment modulated the expression of several genes governing adipogenic and osteoblastic (i.e., WNT-pathway-related genes) differentiation of MSCs. Functional studies demonstrated that ATP, under specific culture conditions, stimulated adipogenesis by significantly increasing the lipid accumulation and the expression levels of the adipogenic master gene PPARγ (peroxisome proliferator-activated receptor-gamma). In addition, ATP stimulated osteogenic differentiation by promoting mineralization and expression of the osteoblast-related gene RUNX2 (runt-related transcription factor 2). Furthermore, we demonstrated that ATP stimulated adipogenesis via its triphosphate form, while osteogenic differentiation was induced by the nucleoside adenosine, resulting from ATP degradation induced by CD39 and CD73 ectonucleotidases expressed on the MSC membrane. The pharmacological profile of P2 purinergic receptors (P2Rs) suggests that adipogenic differentiation is mainly mediated by the engagement of P2Y1 and P2Y4 receptors, while stimulation of the P1R adenosine-specific subtype A2B is involved in adenosine-induced osteogenic differentiation. Thus, we provide new insights into molecular regulation of MSC differentiation.
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Affiliation(s)
- Marilena Ciciarello
- Department of Hematology and Oncological Sciences, L. & A. Seràgnoli, Institute of Hematology, Stem Cell Research Center, Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy.
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Delgado-Calle J, Garmilla P, Riancho JA. Do epigenetic marks govern bone mass and homeostasis? Curr Genomics 2012; 13:252-63. [PMID: 23115526 PMCID: PMC3382279 DOI: 10.2174/138920212800543129] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2011] [Revised: 12/03/2011] [Accepted: 12/09/2011] [Indexed: 12/26/2022] Open
Abstract
Bone is a specialized connective tissue with a calcified extracellular matrix in which cells are embedded. Besides providing the internal support of the body and protection for vital organs, bone also has several important metabolic functions, especially in mineral homeostasis. Far from being a passive tissue, it is continuously being resorbed and formed again throughout life, by a process known as bone remodeling. Bone development and remodeling are influenced by many factors, some of which may be modifiable in the early steps of life. Several studies have shown that environmental factors in uterus and in infancy may modify the skeletal growth pattern, influencing the risk of bone disease in later life. On the other hand, bone remodeling is a highly orchestrated multicellular process that requires the sequential and balanced events of osteoclast-mediated bone resorption and osteoblast-mediated bone formation. These processes are accompanied by specific gene expression patterns which are responsible for the differentiation of the mesenchymal and hematopoietic precursors of osteoblasts and osteoclasts, respectively, and the activity of differentiated bone cells. This review summarizes the current understanding of how epigenetic mechanisms influence these processes and their possible role in common skeletal diseases.
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Affiliation(s)
- Jesús Delgado-Calle
- Department of Internal Medicine, Hospital U.M. Valdecilla-IFIMAV-University of Cantabria, Santander, Spain
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42
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Abstract
Tissue and organ differentiation is tightly controlled to ensure proper development and function of the growing embryo as well as cells such as lymphocytes that differentiate throughout the adult stage. Therefore it is vital that the genes and the protein they encode that are involved in these processes function accurately. Hence, any mutation or error that occurs along the way can result in extensive damage, which is expressed in various ways in the embryo and can result in immune pathogenesis, including immunodeficiency and autoimmune diseases, when lymphocyte development is altered. A number of studies have been carried out to look at the genes regulating transcription in tissue differentiation, including the transcription factors Pbx1. This gene is of particular interest to us as we have identified that it is associated with systemic lupus erythematosus susceptibility (Cuda et al., in press). This perspective summarizes the known roles of Pbx1 in tissue differentiation as well as our recent findings associating genetic variations in Pbx1 to lupus susceptibility, and we will speculate on how this gene controls the maintenance of immune tolerance in T cells.
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Affiliation(s)
- Mayami Sengupta
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610 USA
| | - Laurence Morel
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610 USA
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Chen JR, Zhang J, Lazarenko OP, Kang P, Blackburn ML, Ronis MJJ, Badger TM, Shankar K. Inhibition of fetal bone development through epigenetic down-regulation of HoxA10 in obese rats fed high-fat diet. FASEB J 2011; 26:1131-41. [PMID: 22131269 DOI: 10.1096/fj.11-197822] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Epidemiological studies show that maternal obesity during intrauterine and early postnatal life increases the risk of low bone mass and fracture later in life. Here, we show that bone development is inhibited in gestational embryonic day 18.5 (E18.5) embryos from rat dams made obese by feeding a high-fat diet (HFD). Moreover, fetal rat osteogenic calvarial cells (FOCCs) from these obese dams have significantly less potential to develop into mature osteoblasts compared to cells from AIN-93G diet-fed controls. Profiling of transcriptional genes for osteogenesis revealed a profound decrease in the homeodomain-containing factor A10 (HoxA10) in FOCCs from fetuses of HFD-induced obese dams. Significant methylation of the HoxA10 promoter was found in those FOCCs, as well as in mouse ST2 cells treated with a mixture of free fatty acids similar to that found in serum from HFD-induced obese rats. This was accompanied by lower expression of osteogenic markers, but higher levels of PPARγ. Control FOCCs depleted of the HoxA10 gene (shRNA) ex vivo behave similarly to cells from fetuses of obese dams; conversely, overexpression of HoxA10 gene in FOCCs from HFD rats exhibit the same phenotype as controls. Treatment of FOCCs from control rats or of ST2 cells with an artificial mixture of free fatty acids significantly down-regulated HoxA10 protein expression, and cells exhibited adipocyte-like properties. These results suggest that maternal obesity impairs fetal skeletal development through down-regulation of the HoxA10 gene, which may lead to an increase in the prevalence of low bone mass in the offspring later in life.
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Affiliation(s)
- Jin-Ran Chen
- Arkansas Children's Nutrition Center, 15 Children's Way, Slot 512-20B, Little Rock, AR 72202, USA.
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Emerging roles for retinoids in regeneration and differentiation in normal and disease states. Biochim Biophys Acta Mol Cell Biol Lipids 2011; 1821:213-21. [PMID: 21855651 DOI: 10.1016/j.bbalip.2011.08.002] [Citation(s) in RCA: 118] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 07/29/2011] [Accepted: 08/02/2011] [Indexed: 12/22/2022]
Abstract
The vitamin A (retinol) metabolite, all-trans retinoic acid (RA), is a signaling molecule that plays key roles in the development of the body plan and induces the differentiation of many types of cells. In this review the physiological and pathophysiological roles of retinoids (retinol and related metabolites) in mature animals are discussed. Both in the developing embryo and in the adult, RA signaling via combinatorial Hox gene expression is important for cell positional memory. The genes that require RA for the maturation/differentiation of T cells are only beginning to be cataloged, but it is clear that retinoids play a major role in expression of key genes in the immune system. An exciting, recent publication in regeneration research shows that ALDH1a2 (RALDH2), which is the rate-limiting enzyme in the production of RA from retinaldehyde, is highly induced shortly after amputation in the regenerating heart, adult fin, and larval fin in zebrafish. Thus, local generation of RA presumably plays a key role in fin formation during both embryogenesis and in fin regeneration. HIV transgenic mice and human patients with HIV-associated kidney disease exhibit a profound reduction in the level of RARβ protein in the glomeruli, and HIV transgenic mice show reduced retinol dehydrogenase levels, concomitant with a greater than 3-fold reduction in endogenous RA levels in the glomeruli. Levels of endogenous retinoids (those synthesized from retinol within cells) are altered in many different diseases in the lung, kidney, and central nervous system, contributing to pathophysiology. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.
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