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1
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Bangru S, Chen J, Baker N, Das D, Chembazhi UV, Derham JM, Chorghade S, Arif W, Alencastro F, Duncan AW, Carstens RP, Kalsotra A. ESRP2-microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation. Genes Dev 2025; 39:325-347. [PMID: 39794125 PMCID: PMC11874994 DOI: 10.1101/gad.352129.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 12/17/2024] [Indexed: 01/13/2025]
Abstract
Hepatocyte polyploidy and maturity are critical to acquiring specialized liver functions. Multiple intracellular and extracellular factors influence ploidy, but how they cooperate temporally to steer liver polyploidization and maturation or how post-transcriptional mechanisms integrate into these paradigms is unknown. Here, we identified an important regulatory hierarchy in which postnatal activation of epithelial splicing regulatory protein 2 (ESRP2) stimulates processing of liver-specific microRNA (miR-122) to facilitate polyploidization, maturation, and functional competence of hepatocytes. By determining transcriptome-wide protein-RNA interactions in vivo and integrating them with single-cell and bulk hepatocyte RNA-seq data sets, we delineated an ESRP2-driven RNA processing program that drives sequential replacement of fetal-to-adult transcript isoforms. Specifically, ESRP2 binds the primary miR-122 host gene transcript to promote its processing/biogenesis. Combining constitutive and inducible ESRP2 gain- and loss-of-function mouse models with miR-122 rescue experiments, we demonstrated that timed activation of ESRP2 augments the miR-122-driven program of cytokinesis failure, ensuring the proper onset and extent of hepatocyte polyploidization.
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Affiliation(s)
- Sushant Bangru
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
- Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Jackie Chen
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Nicholas Baker
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
- Carl R. Woese Institute of Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Diptatanu Das
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
- Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
- Chan Zuckerberg Biohub, Chicago, Illinois 60642, USA
| | - Ullas V Chembazhi
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Jessica M Derham
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
- Chan Zuckerberg Biohub, Chicago, Illinois 60642, USA
| | - Sandip Chorghade
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Waqar Arif
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Frances Alencastro
- Department of Pathology, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
| | - Andrew W Duncan
- Department of Pathology, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
| | - Russ P Carstens
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Auinash Kalsotra
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA;
- Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
- Carl R. Woese Institute of Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
- Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, USA
- Chan Zuckerberg Biohub, Chicago, Illinois 60642, USA
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2
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Guo P, Mao L, Chen Y, Lee CN, Cardilla A, Li M, Bartosovic M, Deng Y. Multiplexed spatial mapping of chromatin features, transcriptome and proteins in tissues. Nat Methods 2025; 22:520-529. [PMID: 39870864 PMCID: PMC11906265 DOI: 10.1038/s41592-024-02576-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 12/03/2024] [Indexed: 01/29/2025]
Abstract
The phenotypic and functional states of cells are modulated by a complex interactive molecular hierarchy of multiple omics layers, involving the genome, epigenome, transcriptome, proteome and metabolome. Spatial omics approaches have enabled the study of these layers in tissue context but are often limited to one or two modalities, offering an incomplete view of cellular identity. Here we present spatial-Mux-seq, a multimodal spatial technology that allows simultaneous profiling of five different modalities: two histone modifications, chromatin accessibility, whole transcriptome and a panel of proteins at tissue scale and cellular level in a spatially resolved manner. We applied this technology to mouse embryos and mouse brains, generating detailed multimodal tissue maps that identified more cell types and states compared to unimodal data. This analysis uncovered spatiotemporal relationships among histone modifications, chromatin accessibility, gene expression and protein levels during neuron differentiation, and revealed a radial glia niche with spatially dynamic epigenetic signals. Collectively, the spatial multi-omics approach heralds a new era for characterizing tissue and cellular heterogeneity that single-modality studies alone could not reveal.
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Affiliation(s)
- Pengfei Guo
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Liran Mao
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Statistical Center for Single-Cell and Spatial Genomics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Yufan Chen
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Chin Nien Lee
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Angelysia Cardilla
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Mingyao Li
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Statistical Center for Single-Cell and Spatial Genomics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marek Bartosovic
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
| | - Yanxiang Deng
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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3
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Ferrando-Marco M, Barkoulas M. EFL-3/E2F7 modulates Wnt signalling by repressing the Nemo-like kinase LIT-1 during asymmetric epidermal cell division in Caenorhabditis elegans. Development 2025; 152:DEV204546. [PMID: 40026193 PMCID: PMC11925398 DOI: 10.1242/dev.204546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 02/02/2025] [Indexed: 03/04/2025]
Abstract
The E2F family of transcription factors is conserved in higher eukaryotes and plays pivotal roles in controlling gene expression during the cell cycle. Most canonical E2Fs associate with members of the Dimerisation Partner (DP) family to activate or repress target genes. However, atypical repressors, such as E2F7 and E2F8, lack DP interaction domains and their functions are less understood. We report here that EFL-3, the E2F7 homologue of Caenorhabditis elegans, regulates epidermal stem cell differentiation. We show that phenotypic defects in efl-3 mutants depend on the Nemo-like kinase LIT-1. EFL-3 represses lit-1 expression through direct binding to a lit-1 intronic element. Increased LIT-1 expression in efl-3 mutants reduces POP-1/TCF nuclear distribution, and consequently alters Wnt pathway activation. Our findings provide a mechanistic link between an atypical E2F family member and NLK during C. elegans asymmetric cell division, which may be conserved in other animals.
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4
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Yuan G, Yu C, Du X, Li D, Dou H, Lu P, Wu T, Hao C, Wang Y. Injectable GelMA Hydrogel Microspheres with Sustained Release of Platelet-Rich Plasma for the Treatment of Thin Endometrium. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2403890. [PMID: 39206600 DOI: 10.1002/smll.202403890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/02/2024] [Indexed: 09/04/2024]
Abstract
Platelet-rich plasma (PRP) intrauterine infusion has been demonstrated to be effective in treating thin endometrium and achieving pregnancy. However, the rapid release of growth factors limits its effectiveness in clinical applications, and thus, multiple intrauterine infusions are often required to achieve therapeutic efficacy. In this study, a GelMA hydrogel microsphere biomaterial is developed using droplet microfluidics to modify the delivery mode of PRP and thus prolong its duration of action. Its biocompatibility is confirmed through both in vivo and in vitro studies. Cell experiments show that PRP-loaded microspheres significantly enhance cell proliferation, migration, and angiogenesis. In vivo experiments show that the effects of PRP-loaded microspheres on repairing the endometrium and restoring fertility in mice could achieve the impact of triple PRP intrauterine infusions. Further mechanistic investigations reveal that PRP could facilitate endometrial repair by regulating the expression of E2Fs, a group of transcription factors. This study demonstrates that hydrogel microspheres could modify the delivery of PRP and prolong its duration of action, enabling endometrial repair and functional reconstruction. This design avoids repeated intrauterine injections of PRP in the clinic, reduces the number of patient visits, and provides a new avenue for clinical treatment of thin endometrium.
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Affiliation(s)
- Guanghui Yuan
- Centre for Reproductive Medicine, Women and Children's Hospital, Qingdao University, Qingdao, 266011, China
- Branch of Shandong Provincial Clinical Research Center for Reproductive Health, Qingdao, 266011, China
| | - Chenghao Yu
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266000, China
| | - Xin Du
- Centre for Reproductive Medicine, Women and Children's Hospital, Qingdao University, Qingdao, 266011, China
- Branch of Shandong Provincial Clinical Research Center for Reproductive Health, Qingdao, 266011, China
| | - Duan Li
- Centre for Reproductive Medicine, Women and Children's Hospital, Qingdao University, Qingdao, 266011, China
- Branch of Shandong Provincial Clinical Research Center for Reproductive Health, Qingdao, 266011, China
| | - Huaiqian Dou
- Centre for Reproductive Medicine, Women and Children's Hospital, Qingdao University, Qingdao, 266011, China
- Branch of Shandong Provincial Clinical Research Center for Reproductive Health, Qingdao, 266011, China
| | - Panpan Lu
- Centre for Reproductive Medicine, Women and Children's Hospital, Qingdao University, Qingdao, 266011, China
- Branch of Shandong Provincial Clinical Research Center for Reproductive Health, Qingdao, 266011, China
| | - Tong Wu
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266000, China
- Shandong Key Laboratory of Medical and Health Textile Materials, College of Textile & Clothing, Qingdao University, Qingdao, 266071, China
| | - Cuifang Hao
- Centre for Reproductive Medicine, Women and Children's Hospital, Qingdao University, Qingdao, 266011, China
- Branch of Shandong Provincial Clinical Research Center for Reproductive Health, Qingdao, 266011, China
| | - Yuanfei Wang
- Qingdao Stomatological Hospital Affiliated to Qingdao University, Qingdao, 266001, China
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5
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Guo P, Mao L, Chen Y, Lee CN, Cardilla A, Li M, Bartosovic M, Deng Y. Multiplexed spatial mapping of chromatin features, transcriptome, and proteins in tissues. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.13.612892. [PMID: 39345645 PMCID: PMC11429933 DOI: 10.1101/2024.09.13.612892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
The phenotypic and functional states of a cell are modulated by a complex interactive molecular hierarchy of multiple omics layers, involving the genome, epigenome, transcriptome, proteome, and metabolome. Spatial omics approaches have enabled the capture of information from different molecular layers directly in the tissue context. However, current technologies are limited to map one to two modalities at the same time, providing an incomplete representation of cellular identity. Such data is inadequate to fully understand complex biological systems and their underlying regulatory mechanisms. Here we present spatial-Mux-seq, a multi-modal spatial technology that allows simultaneous profiling of five different modalities, including genome-wide profiles of two histone modifications and open chromatin, whole transcriptome, and a panel of proteins at tissue scale and cellular level in a spatially resolved manner. We applied this technology to generate multi-modal tissue maps in mouse embryos and mouse brains, which discriminated more cell types and states than unimodal data. We investigated the spatiotemporal relationship between histone modifications, chromatin accessibility, gene and protein expression in neuron differentiation revealing the relationship between tissue organization, function, and gene regulatory networks. We were able to identify a radial glia spatial niche and revealed spatially changing gradient of epigenetic signals in this region. Moreover, we revealed previously unappreciated involvement of repressive histone marks in the mouse hippocampus. Collectively, the spatial multi-omics approach heralds a new era for characterizing tissue and cellular heterogeneity that single modality studies alone could not reveal.
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Affiliation(s)
- Pengfei Guo
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- These authors contributed equally
| | - Liran Mao
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Statistical Center for Single-Cell and Spatial Genomics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- These authors contributed equally
| | - Yufan Chen
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Chin Nien Lee
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Angelysia Cardilla
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Mingyao Li
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Statistical Center for Single-Cell and Spatial Genomics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marek Bartosovic
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Yanxiang Deng
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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6
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Darmasaputra GS, Geerlings CC, Chuva de Sousa Lopes SM, Clevers H, Galli M. Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase. J Cell Biol 2024; 223:e202403020. [PMID: 38727809 PMCID: PMC11090133 DOI: 10.1083/jcb.202403020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/24/2024] [Accepted: 04/26/2024] [Indexed: 05/15/2024] Open
Abstract
Binucleated polyploid cells are common in many animal tissues, where they arise by endomitosis, a non-canonical cell cycle in which cells enter M phase but do not undergo cytokinesis. Different steps of cytokinesis have been shown to be inhibited during endomitosis M phase in rodents, but it is currently unknown how human cells undergo endomitosis. In this study, we use fetal-derived human hepatocyte organoids (Hep-Orgs) to investigate how human hepatocytes initiate and execute endomitosis. We find that cells in endomitosis M phase have normal mitotic timings, but lose membrane anchorage to the midbody during cytokinesis, which is associated with the loss of four cortical anchoring proteins, RacGAP1, Anillin, SEPT9, and citron kinase (CIT-K). Moreover, reduction of WNT activity increases the percentage of binucleated cells in Hep-Orgs, an effect that is dependent on the atypical E2F proteins, E2F7 and E2F8. Together, we have elucidated how hepatocytes undergo endomitosis in human Hep-Orgs, providing new insights into the mechanisms of endomitosis in mammals.
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Affiliation(s)
- Gabriella S. Darmasaputra
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, Netherlands
| | - Cindy C. Geerlings
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, Netherlands
| | | | - Hans Clevers
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Matilde Galli
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Utrecht, Netherlands
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7
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Lee J, Miyagishima SY, Bhattacharya D, Yoon HS. From dusk till dawn: cell cycle progression in the red seaweed Gracilariopsis chorda (Rhodophyta). iScience 2024; 27:110190. [PMID: 38984202 PMCID: PMC11231608 DOI: 10.1016/j.isci.2024.110190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 04/29/2024] [Accepted: 06/03/2024] [Indexed: 07/11/2024] Open
Abstract
The conserved eukaryotic functions of cell cycle genes have primarily been studied using animal/plant models and unicellular algae. Cell cycle progression and its regulatory components in red (Rhodophyta) seaweeds are poorly understood. We analyzed diurnal gene expression data to investigate the cell cycle in the red seaweed Gracilariopsis chorda. We identified cell cycle progression and transitions in G. chorda which are induced by interactions of key regulators such as E2F/DP, RBR, cyclin-dependent kinases, and cyclins from dusk to dawn. However, several typical CDK inhibitor proteins are absent in red seaweeds. Interestingly, the G1-S transition in G. chorda is controlled by delayed transcription of GINS subunit 3. We propose that the delayed S phase entry in this seaweed may have evolved to minimize DNA damage (e.g., due to UV radiation) during replication. Our results provide important insights into cell cycle-associated physiology and its molecular mechanisms in red seaweeds.
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Affiliation(s)
- JunMo Lee
- Department of Oceanography, Kyungpook National University, Daegu 41566, Korea
- Kyungpook Institute of Oceanography, Kyungpook National University, Daegu 41566, Korea
| | - Shin-ya Miyagishima
- Department of Gene Function and Phenomics, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan
- Department of Genetics, Graduate University for Advanced Studies, SOKENDAI, Mishima, Shizuoka 411-8540, Japan
| | - Debashish Bhattacharya
- Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, NJ 08901, USA
| | - Hwan Su Yoon
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
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8
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Bangru S, Chen J, Baker N, Das D, Chembazhi UV, Derham JM, Chorghade S, Arif W, Alencastro F, Duncan AW, Carstens RP, Kalsotra A. ESRP2-microRNA-122 axis directs the postnatal onset of liver polyploidization and maturation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.06.602336. [PMID: 39026848 PMCID: PMC11257421 DOI: 10.1101/2024.07.06.602336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Hepatocyte polyploidy and maturity are critical to acquiring specialized liver functions. Multiple intra- and extracellular factors influence ploidy, but how they cooperate temporally to steer liver polyploidization and maturation or how post-transcriptional mechanisms integrate into these paradigms is unknown. Here, we identified an important regulatory hierarchy in which postnatal activation of Epithelial-Splicing-Regulatory-Protein-2 (ESRP2) stimulates biogenesis of liver-specific microRNA (miR-122), thereby facilitating polyploidization, maturation, and functional competence of hepatocytes. By determining transcriptome-wide protein-RNA interactions in vivo and integrating them with single-cell and bulk hepatocyte RNA-seq datasets, we delineate an ESRP2-driven RNA processing program that drives sequential replacement of fetal-to-adult transcript isoforms. Specifically, ESRP2 binds the primary miR-122 host gene transcript to promote its processing/biogenesis. Combining constitutive and inducible ESRP2 gain- and loss-of-function mice models with miR-122 rescue experiments, we demonstrate that timed activation of ESRP2 augments miR-122-driven program of cytokinesis failure, ensuring proper onset and extent of hepatocyte polyploidization.
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9
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Cho CJ, Brown JW, Mills JC. Origins of cancer: ain't it just mature cells misbehaving? EMBO J 2024; 43:2530-2551. [PMID: 38773319 PMCID: PMC11217308 DOI: 10.1038/s44318-024-00099-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 03/15/2024] [Accepted: 03/22/2024] [Indexed: 05/23/2024] Open
Abstract
A pervasive view is that undifferentiated stem cells are alone responsible for generating all other cells and are the origins of cancer. However, emerging evidence demonstrates fully differentiated cells are plastic, can be coaxed to proliferate, and also play essential roles in tissue maintenance, regeneration, and tumorigenesis. Here, we review the mechanisms governing how differentiated cells become cancer cells. First, we examine the unique characteristics of differentiated cell division, focusing on why differentiated cells are more susceptible than stem cells to accumulating mutations. Next, we investigate why the evolution of multicellularity in animals likely required plastic differentiated cells that maintain the capacity to return to the cell cycle and required the tumor suppressor p53. Finally, we examine an example of an evolutionarily conserved program for the plasticity of differentiated cells, paligenosis, which helps explain the origins of cancers that arise in adults. Altogether, we highlight new perspectives for understanding the development of cancer and new strategies for preventing carcinogenic cellular transformations from occurring.
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Affiliation(s)
- Charles J Cho
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Jeffrey W Brown
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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10
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Choksi SP, Byrnes LE, Konjikusic MJ, Tsai BWH, Deleon R, Lu Q, Westlake CJ, Reiter JF. An alternative cell cycle coordinates multiciliated cell differentiation. Nature 2024; 630:214-221. [PMID: 38811726 DOI: 10.1038/s41586-024-07476-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 04/26/2024] [Indexed: 05/31/2024]
Abstract
The canonical mitotic cell cycle coordinates DNA replication, centriole duplication and cytokinesis to generate two cells from one1. Some cells, such as mammalian trophoblast giant cells, use cell cycle variants like the endocycle to bypass mitosis2. Differentiating multiciliated cells, found in the mammalian airway, brain ventricles and reproductive tract, are post-mitotic but generate hundreds of centrioles, each of which matures into a basal body and nucleates a motile cilium3,4. Several cell cycle regulators have previously been implicated in specific steps of multiciliated cell differentiation5,6. Here we show that differentiating multiciliated cells integrate cell cycle regulators into a new alternative cell cycle, which we refer to as the multiciliation cycle. The multiciliation cycle redeploys many canonical cell cycle regulators, including cyclin-dependent kinases (CDKs) and their cognate cyclins. For example, cyclin D1, CDK4 and CDK6, which are regulators of mitotic G1-to-S progression, are required to initiate multiciliated cell differentiation. The multiciliation cycle amplifies some aspects of the canonical cell cycle, such as centriole synthesis, and blocks others, such as DNA replication. E2F7, a transcriptional regulator of canonical S-to-G2 progression, is expressed at high levels during the multiciliation cycle. In the multiciliation cycle, E2F7 directly dampens the expression of genes encoding DNA replication machinery and terminates the S phase-like gene expression program. Loss of E2F7 causes aberrant acquisition of DNA synthesis in multiciliated cells and dysregulation of multiciliation cycle progression, which disrupts centriole maturation and ciliogenesis. We conclude that multiciliated cells use an alternative cell cycle that orchestrates differentiation instead of controlling proliferation.
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Affiliation(s)
- Semil P Choksi
- Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
| | - Lauren E Byrnes
- Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Mia J Konjikusic
- Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Benedict W H Tsai
- Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Rachel Deleon
- Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Quanlong Lu
- Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
| | - Christopher J Westlake
- Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
| | - Jeremy F Reiter
- Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
- Chan Zuckerberg Biohub, San Francisco, CA, USA.
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11
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Herriage HC, Huang YT, Calvi BR. The antagonistic relationship between apoptosis and polyploidy in development and cancer. Semin Cell Dev Biol 2024; 156:35-43. [PMID: 37331841 PMCID: PMC10724375 DOI: 10.1016/j.semcdb.2023.05.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 05/23/2023] [Accepted: 05/30/2023] [Indexed: 06/20/2023]
Abstract
One of the important functions of regulated cell death is to prevent cells from inappropriately acquiring extra copies of their genome, a state known as polyploidy. Apoptosis is the primary cell death mechanism that prevents polyploidy, and defects in this apoptotic response can result in polyploid cells whose subsequent error-prone chromosome segregation are a major contributor to genome instability and cancer progression. Conversely, some cells actively repress apoptosis to become polyploid as part of normal development or regeneration. Thus, although apoptosis prevents polyploidy, the polyploid state can actively repress apoptosis. In this review, we discuss progress in understanding the antagonistic relationship between apoptosis and polyploidy in development and cancer. Despite recent advances, a key conclusion is that much remains unknown about the mechanisms that link apoptosis to polyploid cell cycles. We suggest that drawing parallels between the regulation of apoptosis in development and cancer could help to fill this knowledge gap and lead to more effective therapies.
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Affiliation(s)
- Hunter C Herriage
- Department of Biology, Indiana University, Bloomington, IN 47405, USA
| | - Yi-Ting Huang
- Department of Biology, Indiana University, Bloomington, IN 47405, USA
| | - Brian R Calvi
- Department of Biology, Indiana University, Bloomington, IN 47405, USA.
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12
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Darmasaputra GS, van Rijnberk LM, Galli M. Functional consequences of somatic polyploidy in development. Development 2024; 151:dev202392. [PMID: 38415794 PMCID: PMC10946441 DOI: 10.1242/dev.202392] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/29/2024]
Abstract
Polyploid cells contain multiple genome copies and arise in many animal tissues as a regulated part of development. However, polyploid cells can also arise due to cell division failure, DNA damage or tissue damage. Although polyploidization is crucial for the integrity and function of many tissues, the cellular and tissue-wide consequences of polyploidy can be very diverse. Nonetheless, many polyploid cell types and tissues share a remarkable similarity in function, providing important information about the possible contribution of polyploidy to cell and tissue function. Here, we review studies on polyploid cells in development, underlining parallel functions between different polyploid cell types, as well as differences between developmentally-programmed and stress-induced polyploidy.
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Affiliation(s)
- Gabriella S. Darmasaputra
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, the Netherlands
| | - Lotte M. van Rijnberk
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, the Netherlands
| | - Matilde Galli
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, the Netherlands
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13
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Buddell T, Purdy AL, Patterson M. The genetics of cardiomyocyte polyploidy. Curr Top Dev Biol 2024; 156:245-295. [PMID: 38556425 DOI: 10.1016/bs.ctdb.2024.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
The regulation of ploidy in cardiomyocytes is a complex and tightly regulated aspect of cardiac development and function. Cardiomyocyte ploidy can range from diploid (2N) to 8N or even 16N, and these states change during key stages of development and disease progression. Polyploidization has been associated with cellular hypertrophy to support normal growth of the heart, increased contractile capacity, and improved stress tolerance in the heart. Conversely, alterations to ploidy also occur during cardiac pathogenesis of diseases, such as ischemic and non-ischemic heart failure and arrhythmia. Therefore, understanding which genes control and modulate cardiomyocyte ploidy may provide mechanistic insight underlying cardiac growth, regeneration, and disease. This chapter summarizes the current knowledge regarding the genes involved in the regulation of cardiomyocyte ploidy. We discuss genes that have been directly tested for their role in cardiomyocyte polyploidization, as well as methodologies used to identify ploidy alterations. These genes encode cell cycle regulators, transcription factors, metabolic proteins, nuclear scaffolding, and components of the sarcomere, among others. The general physiological and pathological phenotypes in the heart associated with the genetic manipulations described, and how they coincide with the respective cardiomyocyte ploidy alterations, are further discussed in this chapter. In addition to being candidates for genetic-based therapies for various cardiac maladies, these genes and their functions provide insightful evidence regarding the purpose of widespread polyploidization in cardiomyocytes.
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Affiliation(s)
- Tyler Buddell
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Alexandra L Purdy
- Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Michaela Patterson
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States.
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14
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Wilson SR, Duncan AW. The Ploidy State as a Determinant of Hepatocyte Proliferation. Semin Liver Dis 2023; 43:460-471. [PMID: 37967885 PMCID: PMC10862383 DOI: 10.1055/a-2211-2144] [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] [Indexed: 11/17/2023]
Abstract
The liver's unique chromosomal variations, including polyploidy and aneuploidy, influence hepatocyte identity and function. Among the most well-studied mammalian polyploid cells, hepatocytes exhibit a dynamic interplay between diploid and polyploid states. The ploidy state is dynamic as hepatocytes move through the "ploidy conveyor," undergoing ploidy reversal and re-polyploidization during proliferation. Both diploid and polyploid hepatocytes actively contribute to proliferation, with diploids demonstrating an enhanced proliferative capacity. This enhanced potential positions diploid hepatocytes as primary drivers of liver proliferation in multiple contexts, including homeostasis, regeneration and repopulation, compensatory proliferation following injury, and oncogenic proliferation. This review discusses the influence of ploidy variations on cellular activity. It presents a model for ploidy-associated hepatocyte proliferation, offering a deeper understanding of liver health and disease with the potential to uncover novel treatment approaches.
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Affiliation(s)
- Sierra R. Wilson
- Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Andrew W. Duncan
- Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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15
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Li ZH, Wang JY, Li XL, Meng SB, Zheng HY, Wang JL, Lei ZY, Lin BL, Zhang J. Mesenchymal stem cell-regulated miRNA-mRNA landscape in acute-on-chronic liver failure. Genomics 2023; 115:110737. [PMID: 37926353 DOI: 10.1016/j.ygeno.2023.110737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/20/2023] [Accepted: 10/30/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) is a major challenge in the field of hepatology. While mesenchymal stem cell (MSC) therapy can improve the prognosis of patients with ACLF, the molecular mechanisms through which MSCs attenuate ACLF remain poorly understood. We performed global miRNA and mRNA expression profiling via next-generation sequencing of liver tissues from MSC-treated ACLF mice to identify important signaling pathways and major factors implicated in ACLF alleviation by MSCs. METHODS Carbon tetrachloride-induced ACLF mice were treated with saline or mouse bone marrow-derived MSCs. Mouse livers were subjected to miRNA and mRNA sequencing. Related signal transduction pathways were obtained through Gene Set Enrichment Analysis. Functional enrichment, protein-protein interaction, and immune infiltration analyses were performed for the differentially expressed miRNA target genes (DETs). Hub miRNA and mRNA associated with liver injury were analyzed using LASSO regression. The expression levels of hub genes were subjected to Pearson's correlation analysis and verified using RT-qPCR. The biological functions of hub genes were verified in vitro. RESULTS The tricarboxylic acid cycle and peroxisome proliferator-activated receptor pathways were activated in the MSC-treated groups. The proportions of liver-infiltrating NK resting cells, M2 macrophages, follicular helper T cells, and other immune cells were altered after MSC treatment. The expression levels of six miRNAs and 10 transcripts correlated with the degree of liver injury. miR-27a-5p was downregulated in the mouse liver after MSC treatment, while its target gene E2f2 was upregulated. miR-27a-5p inhibited E2F2 expression, suppressed G1/S phase transition and proliferation of hepatocytes, in addition to promoting their apoptosis. CONCLUSIONS This is the first comprehensive analysis of miRNA and mRNA expression in the liver tissue of ACLF mice after MSC treatment. The results revealed global changes in hepatic pathways and immune subpopulations. The miR-27a-5p/E2F2 axis emerged as a central regulator of the MSC-induced attenuation of ACLF. The current findings improve our understanding of the molecular mechanisms through which MSCs alleviate ACLF.
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Affiliation(s)
- Zhi-Hui Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, People's Republic of China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
| | - Jun-Yi Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, People's Republic of China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
| | - Xian-Long Li
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
| | - Shi-Bo Meng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, People's Republic of China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
| | - Hui-Yuan Zheng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, People's Republic of China
| | - Jia-Lei Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, People's Republic of China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
| | - Zi-Ying Lei
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, People's Republic of China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China.
| | - Bing-Liang Lin
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, People's Republic of China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, People's Republic of China.
| | - Jing Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, People's Republic of China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China.
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16
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Liu Z, Wang W, Li X, Zhao J, Zhu H, Que S, He Y, Xu J, Zhou L, Mardinoglu A, Zheng S. Multi-omics network analysis on samples from sequential biopsies reveals vital role of proliferation arrest for Macrosteatosis related graft failure in rats after liver transplantation. Genomics 2023; 115:110748. [PMID: 37984718 DOI: 10.1016/j.ygeno.2023.110748] [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: 06/12/2023] [Revised: 10/12/2023] [Accepted: 11/15/2023] [Indexed: 11/22/2023]
Abstract
To investigate the molecular impact of graft MaS on post-transplant prognosis, based on multi-omics integrative analysis. Rats were fed by methionine-choline deficient diet (MCD) for MaS grafts. Samples were collected from grafts by sequential biopsies. Transcriptomic and metabolomic profilings were assayed. Post-transplant MaS status showed a close association with graft failure. Differentially expressed genes (DEGs) for in-vivo MaS were mainly enriched on pathways of cell cycle and DNA replication. Post-transplant MaS caused arrests of graft regeneration via inhibiting the E2F1 centered network, which was confirmed by an in vitro experiment. Data from metabolomics assays found insufficient serine/creatine which is located on one‑carbon metabolism was responsible for MaS-related GF. Pre-transplant MaS caused severe fibrosis in long-term survivors. DEGs for grafts from long-term survivors with pre-transplant MaS were mainly enriched in pathways of ECM-receptor interaction and focal adhesion. Transcriptional regulatory network analysis confirmed SOX9 as a key transcription factor (TF) for MaS-related fibrosis. Metabolomic assays found elevation of aromatic amino acid (AAA) was a major feature of fibrosis in long-term survivors. Graft MaS in vivo increased post-transplant GF via negative regulations on graft regeneration. Pre-transplant MaS induced severe fibrosis in long-term survivors via activations on ECM-receptor interaction and AAA metabolism.
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Affiliation(s)
- Zhengtao Liu
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, Zhejiang, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Shulan Hospital (Hangzhou), Hangzhou 310 000, China.
| | - Wenchao Wang
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xiang Li
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Junsheng Zhao
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, Zhejiang, China
| | - Hai Zhu
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | | | - Yong He
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jun Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Lin Zhou
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Adil Mardinoglu
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK; Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden.
| | - Shusen Zheng
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, Zhejiang, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Shulan Hospital (Hangzhou), Hangzhou 310 000, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
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17
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Zhang Y, Wang N, Hao F, Chen Y, Fei X, Wang J. Attenuation of binuclear hepatocytes in the paracancerous liver tissue is associated with short-term recurrence of hepatocellular carcinoma post-radical surgery. FASEB J 2023; 37:e23271. [PMID: 37882195 DOI: 10.1096/fj.202301219r] [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: 06/18/2023] [Revised: 09/03/2023] [Accepted: 10/10/2023] [Indexed: 10/27/2023]
Abstract
Short-term recurrence of hepatocellular carcinoma (HCC) after radical resection leads to dismal outcomes. To screen high-recurrence risk patients to provide adjuvant treatment is necessary. Herein, based on our previous research, we further focused on the changes in the abundance of binuclear hepatocytes (ABH) in the paracancerous liver tissue to discuss the relationship between the attenuation of binuclear hepatocytes and postoperative short-term recurrence, by combining with the assessment of the value of a reported independent early recurrence risk factor in HCC, protein induced by vitamin K absence or antagonist-II (PIVKA-II). A cohort of 142 paracancerous liver tissues from HCC patients who received radical resection was collected. Binuclear hepatocytes were reduced in the paracancerous liver tissues, compared with the liver tissues from normal donors. ABH was negatively correlated with clinical features such as tumor size, TNM stages, tumor microsatellite formation, venous invasion, and Alpha-fetoprotein (AFP) level, as well as the expression of E2F7 and Anillin, which are two critical regulators concerning the hepatocyte polyploidization. According to the short-term recurrence information, ABH value was laminated, and univariate and multivariate logistic regression was performed to analyze the relationship between paracancerous ABH and short-term tumor relapse. Simultaneously, the predictive effectiveness of the ABH value was compared with the preoperative PIVKA-II value. As observed, the paracancerous ABH value below 1.5% was found to be an independent risk factor for recurrence. In conclusion, the paracancerous ABH is a credible indicator of short-term recurrence of HCC patients after radical resection, and regular assessment of ABH might help to prevent short-term HCC recurrence.
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Affiliation(s)
- Yifan Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Nan Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Fengjie Hao
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Yongjun Chen
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Xiaochun Fei
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Junqing Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
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18
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Lu TC, Brbić M, Park YJ, Jackson T, Chen J, Kolluru SS, Qi Y, Katheder NS, Cai XT, Lee S, Chen YC, Auld N, Liang CY, Ding SH, Welsch D, D’Souza S, Pisco AO, Jones RC, Leskovec J, Lai EC, Bellen HJ, Luo L, Jasper H, Quake SR, Li H. Aging Fly Cell Atlas identifies exhaustive aging features at cellular resolution. Science 2023; 380:eadg0934. [PMID: 37319212 PMCID: PMC10829769 DOI: 10.1126/science.adg0934] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 05/04/2023] [Indexed: 06/17/2023]
Abstract
Aging is characterized by a decline in tissue function, but the underlying changes at cellular resolution across the organism remain unclear. Here, we present the Aging Fly Cell Atlas, a single-nucleus transcriptomic map of the whole aging Drosophila. We characterized 163 distinct cell types and performed an in-depth analysis of changes in tissue cell composition, gene expression, and cell identities. We further developed aging clock models to predict fly age and show that ribosomal gene expression is a conserved predictive factor for age. Combining all aging features, we find distinctive cell type-specific aging patterns. This atlas provides a valuable resource for studying fundamental principles of aging in complex organisms.
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Affiliation(s)
- Tzu-Chiao Lu
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Maria Brbić
- School of Computer and Communication Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland
| | - Ye-Jin Park
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Program in Development, Disease Models & Therapeutics, Baylor College of Medicine, Houston, TX 77030, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Tyler Jackson
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Program in Cancer Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jiaye Chen
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Program in Quantitative & Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sai Saroja Kolluru
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- Department of Applied Physics, Stanford University, Stanford, CA, USA
- Chan Zuckerberg Biohub, San Francisco CA, USA
| | - Yanyan Qi
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | | | - Xiaoyu Tracy Cai
- Regenerative Medicine, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Seungjae Lee
- Developmental Biology Program, Sloan Kettering Institute, 1275 York Ave, New York, NY 10065, USA
| | - Yen-Chung Chen
- Department of Biology, New York University, New York, NY 10013, USA
| | - Niccole Auld
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Program in Cancer Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chung-Yi Liang
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Sophia H. Ding
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Doug Welsch
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | | | | | - Robert C. Jones
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Jure Leskovec
- Department of Computer Science, Stanford University, Stanford, CA 94305, USA
| | - Eric C. Lai
- Developmental Biology Program, Sloan Kettering Institute, 1275 York Ave, New York, NY 10065, USA
| | - Hugo J. Bellen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Program in Development, Disease Models & Therapeutics, Baylor College of Medicine, Houston, TX 77030, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
| | - Liqun Luo
- Howard Hughes Medical Institute, Department of Biology, Stanford University, Stanford, CA 94305, USA
| | - Heinrich Jasper
- Regenerative Medicine, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Stephen R. Quake
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- Department of Applied Physics, Stanford University, Stanford, CA, USA
- Chan Zuckerberg Biohub, San Francisco CA, USA
| | - Hongjie Li
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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19
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Sanz-Gómez N, González-Álvarez M, De Las Rivas J, de Cárcer G. Whole-Genome Doubling as a source of cancer: how, when, where, and why? Front Cell Dev Biol 2023; 11:1209136. [PMID: 37342233 PMCID: PMC10277508 DOI: 10.3389/fcell.2023.1209136] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 05/24/2023] [Indexed: 06/22/2023] Open
Abstract
Chromosome instability is a well-known hallmark of cancer, leading to increased genetic plasticity of tumoral cells, which favors cancer aggressiveness, and poor prognosis. One of the main sources of chromosomal instability are events that lead to a Whole-Genome Duplication (WGD) and the subsequently generated cell polyploidy. In recent years, several studies showed that WGD occurs at the early stages of cell transformation, which allows cells to later become aneuploid, thus leading to cancer progression. On the other hand, other studies convey that polyploidy plays a tumor suppressor role, by inducing cell cycle arrest, cell senescence, apoptosis, and even prompting cell differentiation, depending on the tissue cell type. There is still a gap in understanding how cells that underwent WGD can overcome the deleterious effect on cell fitness and evolve to become tumoral. Some laboratories in the chromosomal instability field recently explored this paradox, finding biomarkers that modulate polyploid cells to become oncogenic. This review brings a historical view of how WGD and polyploidy impact cell fitness and cancer progression, and bring together the last studies that describe the genes helping cells to adapt to polyploidy.
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Affiliation(s)
- Natalia Sanz-Gómez
- Cell Cycle and Cancer Biomarkers Laboratory, Cancer Biology Department, Instituto de Investigaciones Biomédicas “Alberto Sols“. (IIBM) CSIC-UAM, Madrid, Spain
| | - María González-Álvarez
- Cell Cycle and Cancer Biomarkers Laboratory, Cancer Biology Department, Instituto de Investigaciones Biomédicas “Alberto Sols“. (IIBM) CSIC-UAM, Madrid, Spain
| | - Javier De Las Rivas
- Bioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IBMCC), Consejo Superior de Investigaciones Científicas (CSIC), University of Salamanca (USAL), Salamanca, Spain
| | - Guillermo de Cárcer
- Cell Cycle and Cancer Biomarkers Laboratory, Cancer Biology Department, Instituto de Investigaciones Biomédicas “Alberto Sols“. (IIBM) CSIC-UAM, Madrid, Spain
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20
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Zhou XL, Wei Y, Chen P, Yang X, Lu C, Pan MH. A novel transcription factor, BmZFP67, regulates endomitosis switch by controlling the expression of cyclin B in silk glands. Int J Biol Macromol 2023:124931. [PMID: 37263320 DOI: 10.1016/j.ijbiomac.2023.124931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 04/25/2023] [Accepted: 05/06/2023] [Indexed: 06/03/2023]
Abstract
Endomitosis is involved in developmental processes associated with an increase in metabolic cell activity, which is characterized by repeated rounds of DNA replication without cytokinesis. Endomitosis cells are widespread in protozoa, plants, animals and humans. Endomitosis cell cycle is currently viewed as a variation of the canonical cell cycle and transformed from mitotic cell cycle. However, the meaningful question about how endomitosis transformed from mitosis is still unclear. Herein, we identified a novel transcription factor in silk glands, ZFP67, which is gradually reduced in silk glands during the transition of mitosis to endomitosis. In addition, over-expressed ZFP67 in silk glands led to the transition delayed. And, knock-out of ZFP67 led to abnormal chromatin division and unsuccessful cell division. These data reveled that ZFP67 played an important role in transition of mitosis to endomitosis. Furthermore, ZFP67 can regulate the transcription of cyclin B, a key cyclin related to cell division and G2/M phase, which is demonstrated by chromatin immunoprecipitation and dual luciferase reporter system in this article. In conclusion, it can be speculated that the decreasing expression of ZFP67 in silk glands during the transition stage of mitosis-to-endomitosis resulted in the lack of cyclin B, which further led to unsuccessful cytokinesis and then promoted the transition from mitosis to endomitosis of silk gland cells.
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Affiliation(s)
- Xiao-Lin Zhou
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China
| | - Yi Wei
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China
| | - Peng Chen
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; Key Laboratory for Sericulture Functional Genomics and Biotechnology of Agricultural Ministry, Southwest University, Chongqing 400716, China
| | - Xi Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China
| | - Cheng Lu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; Key Laboratory for Sericulture Functional Genomics and Biotechnology of Agricultural Ministry, Southwest University, Chongqing 400716, China.
| | - Min-Hui Pan
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; Key Laboratory for Sericulture Functional Genomics and Biotechnology of Agricultural Ministry, Southwest University, Chongqing 400716, China.
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21
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Lee DY, Chun JN, Cho M, So I, Jeon JH. Emerging role of E2F8 in human cancer. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166745. [PMID: 37164180 DOI: 10.1016/j.bbadis.2023.166745] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 05/01/2023] [Accepted: 05/02/2023] [Indexed: 05/12/2023]
Abstract
E2F8 is a multifaceted transcription factor that plays a crucial role in mediating the hallmarks of cancer, including sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Aberrant E2F8 expression is associated with poor clinical outcomes in most human cancers. However, E2F8 also exhibits tumor-suppressing activity; thus, the role of E2F8 in cell-fate determination is unclear. In this review, we highlight the recent progress in understanding the role of E2F8 in human cancers, which will contribute to building a conceptual framework and broadening our knowledge pertaining to E2F8. This review provides insight into future challenges and perspectives regarding the translation of biological knowledge into therapeutic strategies for the treatment of cancer.
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Affiliation(s)
- Da Young Lee
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung Nyeo Chun
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea
| | - Minsoo Cho
- Independent researcher, Seoul, Republic of Korea
| | - Insuk So
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea
| | - Ju-Hong Jeon
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea.
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22
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Wang J, Huang X, Zheng D, Li Q, Mei M, Bao S. PRMT5 determines the pattern of polyploidization and prevents liver from cirrhosis and carcinogenesis. J Genet Genomics 2023; 50:87-98. [PMID: 35500745 DOI: 10.1016/j.jgg.2022.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/12/2022] [Accepted: 04/12/2022] [Indexed: 11/25/2022]
Abstract
Human hepatocellular carcinoma (HCC) occurs almost exclusively in cirrhotic livers. Here, we report that hepatic loss of protein arginine methyltransferase 5 (PRMT5) in mice is sufficient to cause cirrhosis and HCC in a clinically relevant way. Furthermore, pathological polyploidization induced by hepatic loss of PRMT5 promotes liver cirrhosis and hepatic tumorigenesis in aged liver. The loss of PRMT5 leads to hyper-accumulation of P21 and endoreplication-dependent formation of pathological mono-nuclear polyploid hepatocytes. PRMT5 and symmetric dimethylation at histone H4 arginine 3 (H4R3me2s) directly associate with chromatin of P21 to suppress its transcription. More importantly, loss of P21 rescues the pathological mono-nuclear polyploidy and prevents PRMT5-deficiency-induced liver cirrhosis and HCC. Thus, our results indicate that PRMT5-mediated symmetric dimethylation at histone H4 arginine 3 (H4R3me2s) is crucial for preventing pathological polyploidization, liver cirrhosis and tumorigenesis in mouse liver.
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Affiliation(s)
- Jincheng Wang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
| | - Xiang Huang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; School of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Daoshan Zheng
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; School of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qiuling Li
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Mei Mei
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Shilai Bao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; School of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
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23
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Wang L, Chen Y, Chen R, Mao F, Sun Z, Liu X. Risk modeling of single-cell transcriptomes reveals the heterogeneity of immune infiltration in hepatocellular carcinoma. J Biol Chem 2023; 299:102948. [PMID: 36708920 PMCID: PMC10011506 DOI: 10.1016/j.jbc.2023.102948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 01/20/2023] [Accepted: 01/23/2023] [Indexed: 01/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies. E2F transcription factors play an important role in the tumorigenesis and progression of HCC, mainly through the RB/E2F pathway. Prognostic models for HCC based on gene signatures have been developed rapidly in recent years; however, their discriminating ability at the single-cell level remains elusive, which could reflect the underlying mechanisms driving the sample bifurcation. In this study, we constructed and validated a predictive model based on E2F expression, successfully stratifying patients with HCC into two groups with different survival risks. Then we used a single-cell dataset to test the discriminating ability of the predictive model on infiltrating T cells, demonstrating remarkable cellular heterogeneity as well as altered cell fates. We identified distinct cell subpopulations with diverse molecular characteristics. We also found that the distribution of cell subpopulations varied considerably across onset stages among patients, providing a fundamental basis for patient-oriented precision evaluation. Moreover, single-sample gene set enrichment analysis revealed that subsets of CD8+ T cells with significantly different cell adhesion levels could be associated with different patterns of tumor cell dissemination. Therefore, our findings linked the conventional prognostic gene signature to the immune microenvironment and cellular heterogeneity at the single-cell level, thus providing deeper insights into the understanding of HCC tumorigenesis.
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Affiliation(s)
- Lu Wang
- Key Laboratory of Developmental Genes and Human Diseases, School of Life Science and Technology, Southeast University, Nanjing, Jiangsu, China
| | - Yifan Chen
- Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Rao Chen
- Department of Sport Medicine, Peking University Third Hospital, Beijing, China
| | - Fengbiao Mao
- Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China; Cancer Center, Peking University Third Hospital, Beijing, China.
| | - Zhongsheng Sun
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China; Institute of Genomic Medicine, Wenzhou Medical University, University Town, Chashan, Wenzhou, Zhejiang, China.
| | - Xiangdong Liu
- Key Laboratory of Developmental Genes and Human Diseases, School of Life Science and Technology, Southeast University, Nanjing, Jiangsu, China.
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24
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Yu Z, Zhang L, Cattaneo P, Guimarães-Camboa N, Fang X, Gu Y, Peterson KL, Bogomolovas J, Cuitino C, Leone GW, Chen J, Evans SM. Increasing Mononuclear Diploid Cardiomyocytes by Loss of E2F Transcription Factor 7/8 Fails to Improve Cardiac Regeneration After Infarct. Circulation 2023; 147:183-186. [PMID: 36622904 PMCID: PMC9988404 DOI: 10.1161/circulationaha.122.061018] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Zhe Yu
- Skaggs School of Pharmacy and Pharmaceutical Sciences (Z.Y., L.Z., S.M.E.), University of California at San Diego, La Jolla
| | - Lunfeng Zhang
- Skaggs School of Pharmacy and Pharmaceutical Sciences (Z.Y., L.Z., S.M.E.), University of California at San Diego, La Jolla
| | - Paola Cattaneo
- Institute of Genetic and Biomedical Research (IRGB), UOS of Milan, National Research Council of Italy (P.C.)
- Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy (P.C.)
- Institute of Cardiovascular Regeneration, Goethe University, Frankfurt, Germany (P.C., N.G.-C.)
- German Center for Cardiovascular Research, Berlin (partner site Frankfurt Rhine-Main) (P.C., N.G.-C.)
| | - Nuno Guimarães-Camboa
- Institute of Cardiovascular Regeneration, Goethe University, Frankfurt, Germany (P.C., N.G.-C.)
- German Center for Cardiovascular Research, Berlin (partner site Frankfurt Rhine-Main) (P.C., N.G.-C.)
| | - Xi Fang
- Department of Medicine (X.F., Y.G., K.L.P., J.B., J.C., S.M.E.), University of California at San Diego, La Jolla
| | - Yusu Gu
- Department of Medicine (X.F., Y.G., K.L.P., J.B., J.C., S.M.E.), University of California at San Diego, La Jolla
| | - Kirk L Peterson
- Department of Medicine (X.F., Y.G., K.L.P., J.B., J.C., S.M.E.), University of California at San Diego, La Jolla
| | - Julius Bogomolovas
- Department of Medicine (X.F., Y.G., K.L.P., J.B., J.C., S.M.E.), University of California at San Diego, La Jolla
| | - Cecilia Cuitino
- Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus (C.C.)
| | - Gustavo W Leone
- Medical College of Wisconsin Cancer Center, Department of Biochemistry, Medical College of Wisconsin, Wauwatosa (G.W.L.)
| | - Ju Chen
- Department of Medicine (X.F., Y.G., K.L.P., J.B., J.C., S.M.E.), University of California at San Diego, La Jolla
| | - Sylvia M Evans
- Skaggs School of Pharmacy and Pharmaceutical Sciences (Z.Y., L.Z., S.M.E.), University of California at San Diego, La Jolla
- Department of Medicine (X.F., Y.G., K.L.P., J.B., J.C., S.M.E.), University of California at San Diego, La Jolla
- Department of Pharmacology (S.M.E.), University of California at San Diego, La Jolla
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25
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Ding D, Braun T. A Tedious Journey: Cardiomyocyte Proliferation Requires More Than S-Phase Entry and Loss of Polyploidization. Circulation 2023; 147:154-157. [PMID: 36622907 DOI: 10.1161/circulationaha.122.062784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Dong Ding
- Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (D.D., T.B.)
| | - Thomas Braun
- Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (D.D., T.B.).,German Center for Cardiovascular Research (DZHK), Rhine Main, Germany (T.B.).,German Center for Lung Research (DZL), Giessen, Germany (T.B.)
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26
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Moreno E, Matondo AB, Bongiovanni L, van de Lest CHA, Molenaar MR, Toussaint MJM, van Essen SC, Houweling M, Helms JB, Westendorp B, de Bruin A. Inhibition of polyploidization in Pten-deficient livers reduces steatosis. Liver Int 2022; 42:2442-2452. [PMID: 35924448 PMCID: PMC9826152 DOI: 10.1111/liv.15384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 07/23/2022] [Accepted: 07/24/2022] [Indexed: 01/11/2023]
Abstract
The tumour suppressor PTEN is a negative regulator of the PI3K/AKT signalling pathway. Liver-specific deletion of Pten in mice results in the hyper-activation PI3K/AKT signalling accompanied by enhanced genome duplication (polyploidization), marked lipid accumulation (steatosis) and formation of hepatocellular carcinomas. However, it is unknown whether polyploidization in this model has an impact on the development of steatosis and the progression towards liver cancer. Here, we used a liver-specific conditional knockout approach to delete Pten in combination with deletion of E2f7/8, known key inducers of polyploidization. As expected, Pten deletion caused severe steatosis and liver tumours accompanied by enhanced polyploidization. Additional deletion of E2f7/8 inhibited polyploidization, alleviated Pten-induced steatosis without affecting lipid species composition and accelerated liver tumour progression. Global transcriptomic analysis showed that inhibition of polyploidization in Pten-deficient livers resulted in reduced expression of genes involved in energy metabolism, including PPAR-gamma signalling. However, we find no evidence that deregulated genes in Pten-deficient livers are direct transcriptional targets of E2F7/8, supporting that reduction in steatosis and progression towards liver cancer are likely consequences of inhibiting polyploidization. Lastly, flow cytometry and image analysis on isolated primary wildtype mouse hepatocytes provided further support that polyploid cells can accumulate more lipid droplets than diploid hepatocytes. Collectively, we show that polyploidization promotes steatosis and function as an important barrier against liver tumour progression in Pten-deficient livers.
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Affiliation(s)
- Eva Moreno
- Departments of Biomolecular Health Sciences, Division Cell Biology, Metabolism & Cancer, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Augustine B. Matondo
- Departments of Biomolecular Health Sciences, Division Cell Biology, Metabolism & Cancer, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Laura Bongiovanni
- Departments of Biomolecular Health Sciences, Division Cell Biology, Metabolism & Cancer, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Chris H. A. van de Lest
- Departments of Biomolecular Health Sciences, Division Cell Biology, Metabolism & Cancer, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Martijn R. Molenaar
- Departments of Biomolecular Health Sciences, Division Cell Biology, Metabolism & Cancer, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Mathilda J. M. Toussaint
- Departments of Biomolecular Health Sciences, Division Cell Biology, Metabolism & Cancer, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Saskia C. van Essen
- Departments of Biomolecular Health Sciences, Division Cell Biology, Metabolism & Cancer, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Martin Houweling
- Departments of Biomolecular Health Sciences, Division Cell Biology, Metabolism & Cancer, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - J. Bernd Helms
- Departments of Biomolecular Health Sciences, Division Cell Biology, Metabolism & Cancer, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Bart Westendorp
- Departments of Biomolecular Health Sciences, Division Cell Biology, Metabolism & Cancer, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Alain de Bruin
- Departments of Biomolecular Health Sciences, Division Cell Biology, Metabolism & Cancer, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands,Pediatrics, Division Molecular GeneticsUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
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27
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Sladky VC, Akbari H, Tapias-Gomez D, Evans LT, Drown CG, Strong MA, LoMastro GM, Larman T, Holland AJ. Centriole signaling restricts hepatocyte ploidy to maintain liver integrity. Genes Dev 2022; 36:gad.349727.122. [PMID: 35981754 PMCID: PMC9480857 DOI: 10.1101/gad.349727.122] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/27/2022] [Indexed: 01/03/2023]
Abstract
Hepatocyte polyploidization is a tightly controlled process that is initiated at weaning and increases with age. The proliferation of polyploid hepatocytes in vivo is restricted by the PIDDosome-P53 axis, but how this pathway is triggered remains unclear. Given that increased hepatocyte ploidy protects against malignant transformation, the evolutionary driver that sets the upper limit for hepatocyte ploidy remains unknown. Here we show that hepatocytes accumulate centrioles during cycles of polyploidization in vivo. The presence of excess mature centrioles containing ANKRD26 was required to activate the PIDDosome in polyploid cells. As a result, mice lacking centrioles in the liver or ANKRD26 exhibited increased hepatocyte ploidy. Under normal homeostatic conditions, this increase in liver ploidy did not impact organ function. However, in response to chronic liver injury, blocking centriole-mediated ploidy control leads to a massive increase in hepatocyte polyploidization, severe liver damage, and impaired liver function. These results show that hyperpolyploidization sensitizes the liver to injury, posing a trade-off for the cancer-protective effect of increased hepatocyte ploidy. Our results may have important implications for unscheduled polyploidization that frequently occurs in human patients with chronic liver disease.
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Affiliation(s)
- Valentina C Sladky
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Hanan Akbari
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Daniel Tapias-Gomez
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Lauren T Evans
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Chelsea G Drown
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Margaret A Strong
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Gina M LoMastro
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Tatianna Larman
- Divison of Gastrointestinal and Liver Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
| | - Andrew J Holland
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
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28
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Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade. Proc Natl Acad Sci U S A 2022; 119:e2203849119. [PMID: 35867815 PMCID: PMC9335208 DOI: 10.1073/pnas.2203849119] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
As a general model for cell cycle control, repressors keep cells quiescent until growth signals remove the inhibition. For S phase, this is exemplified by the Retinoblastoma (RB) protein and its inactivation. It was unknown whether similar mechanisms operate in the M phase. The Wnt signaling pathway is an important regulator of cell proliferation. Here, we find that Wnt induces expression of the transcription factor Tbx3, which in turn represses mitotic inhibitors E2f7 and E2f8 to permit mitotic progression. Such a cascade of transcriptional repressors may be a general mechanism for cell division control. These findings have implications for tissue homeostasis and disease, as the function for Wnt signaling in mitosis is relevant to its widespread role in stem cells and cancer. Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition, allowing cells to divide. In several tissues, including the liver, cell proliferation is inhibited at mitosis by the transcriptional repressors E2F7 and E2F8, leading to formation of polyploid cells. Whether growth factors promote mitosis and cell cycle progression by relieving the E2F7/E2F8-mediated inhibition is unknown. We report here on a mechanism of cell division control in the postnatal liver, in which Wnt/β-catenin signaling maintains active hepatocyte cell division through Tbx3, a Wnt target gene. The TBX3 protein directly represses transcription of E2f7 and E2f8, thereby promoting mitosis. This cascade of sequential transcriptional repressors, initiated by Wnt signals, provides a paradigm for exploring how commonly active developmental signals impact cell cycle completion.
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29
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Kim JY, Choi H, Kim HJ, Jee Y, Noh M, Lee MO. Polyploidization of Hepatocytes: Insights into the Pathogenesis of Liver Diseases. Biomol Ther (Seoul) 2022; 30:391-398. [PMID: 35790893 PMCID: PMC9424332 DOI: 10.4062/biomolther.2022.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 05/27/2022] [Accepted: 05/28/2022] [Indexed: 11/26/2022] Open
Abstract
Polyploidization is a process by which cells are induced to possess more than two sets of chromosomes. Although polyploidization is not frequent in mammals, it is closely associated with development and differentiation of specific tissues and organs. The liver is one of the mammalian organs that displays ploidy dynamics in physiological homeostasis during its development. The ratio of polyploid hepatocytes increases significantly in response to hepatic injury from aging, viral infection, iron overload, surgical resection, or metabolic overload, such as that from non-alcoholic fatty liver diseases (NAFLDs). One of the unique features of NAFLD is the marked heterogeneity of hepatocyte nuclear size, which is strongly associated with an adverse liver-related outcome, such as hepatocellular carcinoma, liver transplantation, and liver-related death. Thus, hepatic polyploidization has been suggested as a potential driver in the progression of NAFLDs that are involved in the control of the multiple pathogenicity of the diseases. However, the importance of polyploidy in diverse pathophysiological contexts remains elusive. Recently, several studies reported successful improvement of symptoms of NAFLDs by reducing pathological polyploidy or by controlling cell cycle progression in animal models, suggesting that better understanding the mechanisms of pathological hepatic polyploidy may provide insights into the treatment of hepatic disorders.
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Affiliation(s)
- Ju-Yeon Kim
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
| | - Haena Choi
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
| | - Hyeon-Ji Kim
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 00826, Republic of Korea
| | - Yelin Jee
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
| | - Minsoo Noh
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 00826, Republic of Korea
| | - Mi-Ock Lee
- College of Pharmacy, Seoul National University, Seoul 00826, Republic of Korea
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 00826, Republic of Korea
- Bio-MAX institute, Seoul National University, Seoul 08826, Republic of Korea
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30
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Du K, Sun S, Jiang T, Liu T, Zuo X, Xia X, Liu X, Wang Y, Bu Y. E2F2 promotes lung adenocarcinoma progression through B-Myb- and FOXM1-facilitated core transcription regulatory circuitry. Int J Biol Sci 2022; 18:4151-4170. [PMID: 35844795 PMCID: PMC9274503 DOI: 10.7150/ijbs.72386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 06/14/2022] [Indexed: 11/15/2022] Open
Abstract
Lung adenocarcinoma (LUAD) causes severe cancer death worldwide. E2F2 is a canonical transcription factor implicated in transcription regulation, cell cycle and tumorigenesis. The role of E2F2 as well as its transcription regulatory network in LUAD remains obscure. In this study, we constructed a weighted gene co-expression network and identified several key modules and networks overrepresented in LUAD, including the E2F2-centered transcription regulatory network. Function analysis revealed that E2F2 overexpression accelerated cell growth, cell cycle progression and cell motility in LUAD cells whereas E2F2 knockdown inhibited these malignant phenotypes. Mechanistic investigations uncovered various E2F2-regulated downstream genes and oncogenic signaling pathways. Notably, three core transcription factors of E2F2, B-Myb and FOXM1 from the LUAD transcription regulatory network exhibited positive expression correlation, associated with each other, mutually transactivated each other, and regulated similar downstream gene cascades, hence constituting a consolidated core transcription regulatory circuitry. Moreover, E2F2 could promote and was essentially required for LUAD growth in orthotopic mouse models. Prognosis modeling revealed that a two-gene signature of E2F2 and PLK1 from the transcription regulatory circuitry remarkably stratified patients into low- and high-risk groups. Collectively, our results clarified the critical roles of E2F2 and the exquisite core transcription regulatory circuitry of E2F2/B-Myb/FOXM1 in LUAD progression.
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Affiliation(s)
- Kailong Du
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Shijie Sun
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Tinghui Jiang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Tao Liu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Xiaofeng Zuo
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Xing Xia
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Xianjun Liu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Yitao Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Youquan Bu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China
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31
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van Rijnberk LM, Barrull-Mascaró R, van der Palen RL, Schild ES, Korswagen HC, Galli M. Endomitosis controls tissue-specific gene expression during development. PLoS Biol 2022; 20:e3001597. [PMID: 35609035 PMCID: PMC9129049 DOI: 10.1371/journal.pbio.3001597] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/09/2022] [Indexed: 11/19/2022] Open
Abstract
Polyploid cells contain more than 2 copies of the genome and are found in many plant and animal tissues. Different types of polyploidy exist, in which the genome is confined to either 1 nucleus (mononucleation) or 2 or more nuclei (multinucleation). Despite the widespread occurrence of polyploidy, the functional significance of different types of polyploidy is largely unknown. Here, we assess the function of multinucleation in Caenorhabditis elegans intestinal cells through specific inhibition of binucleation without altering genome ploidy. Through single-worm RNA sequencing, we find that binucleation is important for tissue-specific gene expression, most prominently for genes that show a rapid up-regulation at the transition from larval development to adulthood. Regulated genes include vitellogenins, which encode yolk proteins that facilitate nutrient transport to the germline. We find that reduced expression of vitellogenins in mononucleated intestinal cells leads to progeny with developmental delays and reduced fitness. Together, our results show that binucleation facilitates rapid up-regulation of intestine-specific gene expression during development, independently of genome ploidy, underscoring the importance of spatial genome organization for polyploid cell function. Why do some cells contain more than one nucleus? By comparing mononucleated and multinucleated polyploid cells in C. elegans, this study shows that having multiple nuclei is important for optimal transcriptional upregulation of developmentally controlled genes.
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Affiliation(s)
- Lotte M. van Rijnberk
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands
| | - Ramon Barrull-Mascaró
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands
| | - Reinier L. van der Palen
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands
| | - Erik S. Schild
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands
| | - Hendrik C. Korswagen
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands
| | - Matilde Galli
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands
- * E-mail:
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32
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PIDD1 in cell cycle control, sterile inflammation and cell death. Biochem Soc Trans 2022; 50:813-824. [PMID: 35343572 PMCID: PMC9162469 DOI: 10.1042/bst20211186] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/06/2022] [Accepted: 03/08/2022] [Indexed: 02/06/2023]
Abstract
The death fold domain-containing protein PIDD1 has recently attracted renewed attention as a regulator of the orphan cell death-related protease, Caspase-2. Caspase-2 can activate p53 to promote cell cycle arrest in response to centrosome aberrations, and its activation requires formation of the PIDDosome multi-protein complex containing multimers of PIDD1 and the adapter RAIDD/CRADD at its core. However, PIDD1 appears to be able to engage with multiple client proteins to promote an even broader range of biological responses, such as NF-κB activation, translesion DNA synthesis or cell death. PIDD1 shows features of inteins, a class of self-cleaving proteins, to create different polypeptides from a common precursor protein that allow it to serve these diverse functions. This review summarizes structural information and molecular features as well as recent experimental advances that highlight the potential pathophysiological roles of this unique death fold protein to highlight its drug-target potential.
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Kim JY, Yang IS, Kim HJ, Yoon JY, Han YH, Seong JK, Lee MO. RORα contributes to the maintenance of genome ploidy in the liver of mice with diet-induced nonalcoholic steatohepatitis. Am J Physiol Endocrinol Metab 2022; 322:E118-E131. [PMID: 34894722 DOI: 10.1152/ajpendo.00309.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hepatic polyploidization is closely linked to the progression of nonalcoholic fatty liver disease (NAFLD); however, the underlying molecular mechanism is not clearly understood. In this study, we demonstrated the role of retinoic acid-related orphan receptor α (RORα) in the maintenance of genomic integrity, particularly in the pathogenesis of NAFLD, using the high-fat diet (HFD)-fed liver-specific RORα knockout (RORα-LKO) mouse model. First, we observed that the loss of hepatic retinoic acid receptor-related orphan receptor α (RORα) accelerated hepatocyte nuclear polyploidization after HFD feeding. In 70% partial hepatectomy experiments, enrichment of hepatocyte polyploidy was more obvious in the RORα-LKO animals, which was accompanied by early progression to the S phase and blockade of the G2/M transition, suggesting a potential role of RORα in suppressing hepatocyte polyploidization in the regenerating liver. An analysis of a publicly available RNA sequencing (RNA-seq) and chromatin immunoprecipitation-seq dataset, together with the Search Tool of the Retrieval of Interacting Genes/Proteins database resource, revealed that DNA endoreplication was the top-enriched biological process Gene Ontology term. Furthermore, we found that E2f7 and E2f8, which encode key transcription factors for DNA endoreplication, were the downstream targets of RORα-induced transcriptional repression. Finally, we showed that the administration of JC1-40, an RORα activator (5 mg/kg body wt), significantly reduced hepatic nuclear polyploidization in the HFD-fed mice. Together, our observations suggest that the RORα-induced suppression of hepatic polyploidization may provide new insights into the pathological polyploidy of NAFLD and may contribute to the development of therapeutic strategies for the treatment of NAFLD.NEW & NOTEWORTHY It has been reported that hepatic polyploidization is closely linked to the progression of NAFLD. Here, we showed that the genetic depletion of hepatic RORα in mice accelerated hepatocyte polyploidization after high-fat diet feeding. The mechanism could be the RORα-mediated repression of E2f7 and E2f8, key transcription factors for DNA endoreplication. Thus, preservation of genome integrity by RORα could provide a new insight for developing therapeutics against the disease.
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Affiliation(s)
- Ju-Yeon Kim
- College of Pharmacy, Seoul National University, Seoul, South Korea
| | - In Sook Yang
- College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Hyeon-Ji Kim
- College of Pharmacy, Seoul National University, Seoul, South Korea
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Jae-Yeun Yoon
- College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Yong-Hyun Han
- College of Pharmacy, Kangwon National University, Chuncheon, South Korea
| | - Je Kyung Seong
- College of Veterinary Medicine, Seoul National University, Seoul, South Korea
- Research Institute of Veterinary Science, Seoul National University, Seoul, South Korea
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, South Korea
| | - Mi-Ock Lee
- College of Pharmacy, Seoul National University, Seoul, South Korea
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
- Bio-MAX Institute, Seoul National University, Seoul, South Korea
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, South Korea
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34
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Wang N, Hao F, Shi Y, Wang J. The Controversial Role of Polyploidy in Hepatocellular Carcinoma. Onco Targets Ther 2021; 14:5335-5344. [PMID: 34866913 PMCID: PMC8636953 DOI: 10.2147/ott.s340435] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/16/2021] [Indexed: 12/21/2022] Open
Abstract
Polyploidy, a physiological phenomenon in which cells contain more than two sets of homologous chromosomes, commonly exists in plants, fish, and amphibians but is rare in mammals. In humans, polyploid cells are detected commonly in specific organs or tissues including the heart, marrow, and liver. As the largest solid organ in the body, the liver is responsible for a myriad of functions, most of which are closely related to polyploid hepatocytes. It has been confirmed that polyploid hepatocytes are related to liver regeneration, homeostasis, terminal differentiation, and aging. Polyploid hepatocytes accumulate during the aging process as well as in chronically injured livers. The relationship between polyploid hepatocytes and hepatocellular carcinoma, the endpoint of most chronic liver diseases, is not yet fully understood. Recently, accumulated evidence has revealed that polyploid involves in the process of tumorigenesis and development. The study of the correlation and relationship between polyploidy hepatocytes and the development of hepatocellular carcinoma can potentially promote the prevention, early diagnosis, and treatment of hepatocellular carcinoma. In this review, we conclude the potential mechanisms of polyploid hepatocytes formation, focusing on the specific biological significance of polyploid hepatocytes. In addition, we examine recent discoveries that have begun to clarify the relevance between polyploid hepatocytes and hepatocellular carcinoma and discuss recent excellent findings that reveal the role of polyploid hepatocytes as resisters of hepatocellular carcinoma or as promoters of hepatocarcinogenesis.
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Affiliation(s)
- Nan Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Fengjie Hao
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yan Shi
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Junqing Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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35
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Sladky VC, Eichin F, Reiberger T, Villunger A. Polyploidy control in hepatic health and disease. J Hepatol 2021; 75:1177-1191. [PMID: 34228992 DOI: 10.1016/j.jhep.2021.06.030] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/25/2021] [Accepted: 06/15/2021] [Indexed: 12/24/2022]
Abstract
A balanced increase in DNA content (ploidy) is observed in some human cell types, including bone-resorbing osteoclasts, platelet-producing megakaryocytes, cardiomyocytes or hepatocytes. The impact of increased hepatocyte ploidy on normal physiology and diverse liver pathologies is still poorly understood. Recent findings suggest swift genetic adaptation to hepatotoxic stress and the protection from malignant transformation as beneficial effects. Herein, we discuss the molecular mechanisms regulating hepatocyte polyploidisation and its implication for different liver diseases and hepatocellular carcinoma. We report on centrosomes' role in limiting polyploidy by activating the p53 signalling network (via the PIDDosome multiprotein complex) and we discuss the role of this pathway in liver disease. Increased hepatocyte ploidy is a hallmark of hepatic inflammation and may play a protective role against liver cancer. Our evolving understanding of hepatocyte ploidy is discussed from the perspective of its potential clinical application for risk stratification, prognosis, and novel therapeutic strategies in liver disease and hepatocellular carcinoma.
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Affiliation(s)
- Valentina C Sladky
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Felix Eichin
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), 1090 Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
| | - Andreas Villunger
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), 1090 Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
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36
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Donne R, Sangouard F, Celton-Morizur S, Desdouets C. Hepatocyte Polyploidy: Driver or Gatekeeper of Chronic Liver Diseases. Cancers (Basel) 2021; 13:cancers13205151. [PMID: 34680300 PMCID: PMC8534039 DOI: 10.3390/cancers13205151] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/11/2021] [Accepted: 10/11/2021] [Indexed: 12/25/2022] Open
Abstract
Polyploidy, also known as whole-genome amplification, is a condition in which the organism has more than two basic sets of chromosomes. Polyploidy frequently arises during tissue development and repair, and in age-associated diseases, such as cancer. Its consequences are diverse and clearly different between systems. The liver is a particularly fascinating organ in that it can adapt its ploidy to the physiological and pathological context. Polyploid hepatocytes are characterized in terms of the number of nuclei per cell (cellular ploidy; mononucleate/binucleate hepatocytes) and the number of chromosome sets in each nucleus (nuclear ploidy; diploid, tetraploid, octoploid). The advantages and disadvantages of polyploidy in mammals are not fully understood. About 30% of the hepatocytes in the human liver are polyploid. In this review, we explore the mechanisms underlying the development of polyploid cells, our current understanding of the regulation of polyploidization during development and pathophysiology and its consequences for liver function. We will also provide data shedding light on the ways in which polyploid hepatocytes cope with centrosome amplification. Finally, we discuss recent discoveries highlighting the possible roles of liver polyploidy in protecting against tumor formation, or, conversely, contributing to liver tumorigenesis.
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Affiliation(s)
- Romain Donne
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029, USA
- Icahn School of Medicine at Mount Sinai, The Precision Immunology Institute, New York, NY 10029, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Flora Sangouard
- Laboratory of Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, F-75006 Paris, France;
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France
| | - Séverine Celton-Morizur
- Laboratory of Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, F-75006 Paris, France;
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France
- Correspondence: (S.C.-M.); (C.D.)
| | - Chantal Desdouets
- Laboratory of Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, F-75006 Paris, France;
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France
- Correspondence: (S.C.-M.); (C.D.)
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37
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Bailey EC, Kobielski S, Park J, Losick VP. Polyploidy in Tissue Repair and Regeneration. Cold Spring Harb Perspect Biol 2021; 13:a040881. [PMID: 34187807 PMCID: PMC8485745 DOI: 10.1101/cshperspect.a040881] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Polyploidy is defined as a cell with three or more whole genome sets and enables cell growth across the kingdoms of life. Studies in model organisms have revealed that polyploid cell growth can be required for optimal tissue repair and regeneration. In mammals, polyploid cell growth contributes to repair of many tissues, including the liver, heart, kidney, bladder, and eye, and similar strategies have been identified in Drosophila and zebrafish tissues. This review discusses the heterogeneity and versatility of polyploidy in tissue repair and regeneration. Polyploidy has been shown to restore tissue mass and maintain organ size as well as protect against oncogenic insults and genotoxic stress. Polyploid cells can also serve as a reservoir for new diploid cells in regeneration. The numerous mechanisms to generate polyploid cells provide an unlimited resource for tissues to exploit to undergo repair or regeneration.
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Affiliation(s)
- Erin C Bailey
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA
| | - Sara Kobielski
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA
| | - John Park
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA
| | - Vicki P Losick
- Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA
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38
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Kim M, Delos Santos K, Moon NS. Proper CycE-Cdk2 activity in endocycling tissues requires regulation of the cyclin-dependent kinase inhibitor Dacapo by dE2F1b in Drosophila. Genetics 2021; 217:1-15. [PMID: 33683365 DOI: 10.1093/genetics/iyaa029] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 12/06/2020] [Indexed: 01/05/2023] Open
Abstract
Polyploidy is an integral part of development and is associated with cellular stress, aging, and pathological conditions. The endocycle, comprised of successive rounds of G and S phases without mitosis, is widely employed to produce polyploid cells in plants and animals. In Drosophila, maintenance of the endocycle is dependent on E2F-governed oscillations of Cyclin E (CycE)-Cdk2 activity, which is known to be largely regulated at the level of transcription. In this study, we report an additional level of E2F-dependent control of CycE-Cdk2 activity during the endocycle. Genetic experiments revealed that an alternative isoform of Drosophila de2f1, dE2F1b, regulates the expression of the p27CIP/KIP-like Cdk inhibitor Dacapo (Dap). We provide evidence showing that dE2F1b-dependent Dap expression in endocycling tissues is necessary for setting proper CycE-Cdk2 activity. Furthermore, we demonstrate that dE2F1b is required for proliferating cell nuclear antigen expression that establishes a negative feedback loop in S phase. Overall, our study reveals previously unappreciated E2F-dependent regulatory networks that are critical for the periodic transition between G and S phases during the endocycle.
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Affiliation(s)
- Minhee Kim
- Department of Biology, Developmental Biology Research Initiative, McGill University, Montreal, Quebec H3A 1B1 Canada
| | - Keemo Delos Santos
- Department of Biology, Developmental Biology Research Initiative, McGill University, Montreal, Quebec H3A 1B1 Canada
| | - Nam-Sung Moon
- Department of Biology, Developmental Biology Research Initiative, McGill University, Montreal, Quebec H3A 1B1 Canada
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39
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Nakano T, Aochi H, Hirasaki M, Takenaka Y, Fujita K, Tamura M, Soma H, Kamezawa H, Koizumi T, Shibuya H, Inomata R, Okuda A, Murakoshi T, Shimada A, Inoue I. Effects of Pparγ1 deletion on late-stage murine embryogenesis and cells that undergo endocycle. Dev Biol 2021; 478:222-235. [PMID: 34246625 DOI: 10.1016/j.ydbio.2021.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 07/01/2021] [Accepted: 07/06/2021] [Indexed: 10/20/2022]
Abstract
Peroxisome proliferator-activated receptor (PPAR) γ1, a nuclear receptor, is abundant in the murine placenta during the late stage of pregnancy (E15-E16), although its functional roles remain unclear. PPARγ1 is encoded by two splicing isoforms, namely Pparγ1canonical and Pparγ1sv, and its embryonic loss leads to early (E10) embryonic lethality. Thus, we generated knockout (KO) mice that carried only one of the isoforms to obtain a milder phenotype. Pparγ1sv-KO mice were viable and fertile, whereas Pparγ1canonical-KO mice failed to recover around the weaning age. Pparγ1canonical-KO embryos developed normally up to 15.5 dpc, followed by growth delays after that. The junctional zone of Pparγ1canonical-KO placentas severely infiltrated the labyrinth, and maternal blood sinuses were dilated. In the wild-type, PPARγ1 was highly expressed in sinusoidal trophoblast giant cells (S-TGCs), peaking at 15.5 dpc. Pparγ1canonical-KO abolished PPARγ1 expression in S-TGCs. Notably, the S-TGCs had unusually enlarged nuclei and often occupied maternal vascular spaces, disturbing the organization of the fine labyrinth structure. Gene expression analyses of Pparγ1canonical-KO placentas indicated enhanced S-phase cell cycle signatures. EdU-positive S-TGCs in Pparγ1canonical-KO placentas were greater in number than those in wild-type placentas, suggesting that the cells continued to endoreplicate in the mutant placentas. These results indicate that PPARγ1, a known cell cycle arrest mediator, is involved in the transition of TGCs undergoing endocycling to the terminal differentiation stage in the placentas. Therefore, PPARγ1 deficiency, induced through genetic manipulation, leads to placental insufficiency.
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Affiliation(s)
- Takanari Nakano
- Department of Biochemistry, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
| | - Hidekazu Aochi
- Department of Anatomy, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Masataka Hirasaki
- Division of Developmental Biology, Research Center for Genomic Medicine, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Yasuhiro Takenaka
- Department of Diabetes and Endocrinology, Faculty of Medicine, Saitama Medical University, Saitama, Japan; Department of Physiology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Koji Fujita
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Masaru Tamura
- Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Research Center, Tsukuba, Ibaraki, Japan
| | - Hiroaki Soma
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan; Department of Obstetrics & Gynecology, Tokyo Medical University, Tokyo, Japan
| | - Hajime Kamezawa
- Department of Anatomy, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Takahiro Koizumi
- Department of Ophthalmology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Hirotoshi Shibuya
- Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Research Center, Tsukuba, Ibaraki, Japan
| | - Reiko Inomata
- Department of Anatomy, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Akihiko Okuda
- Division of Developmental Biology, Research Center for Genomic Medicine, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Takayuki Murakoshi
- Department of Biochemistry, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Akira Shimada
- Department of Diabetes and Endocrinology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Ikuo Inoue
- Department of Diabetes and Endocrinology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
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40
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Liu J, Xia L, Wang S, Cai X, Wu X, Zou C, Shan B, Luo M, Wang D. E2F4 Promotes the Proliferation of Hepatocellular Carcinoma Cells through Upregulation of CDCA3. J Cancer 2021; 12:5173-5180. [PMID: 34335934 PMCID: PMC8317516 DOI: 10.7150/jca.53708] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 06/08/2021] [Indexed: 12/29/2022] Open
Abstract
Liver cancer, the second most commonly diagnosed cancer, is associated with high mortality rates. E2F4 is a member of the E2F transcription factor family. There are limited studies on the role of E2F4 in hepatocellular carcinoma (HCC). In this study, the expression of E2F4 in HCC tissue samples and cell lines was analyzed using quantitative real-time polymerase chain reaction. E2F4 expression positively correlated with tumor size in patients with HCC. Additionally, E2F4 expression was greater in HCC cells than in normal LO2 cells. Furthermore, overexpression of E2F4 significantly enhanced the proliferation, migration, and invasion of HCC cells. The results of a luciferase assay revealed that E2F4 upregulated the expression of CDCA3 by binding to its promoter region (1863'-ACGCGCGAGAATG-1875') and consequently promoted proliferation and cell cycle progression of HCC cells. Taken together, these results demonstrated that E2F4 might play a vital role in HCC progression and could serve as a potential biomarker for the diagnosis and as a therapeutic target of HCC.
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Affiliation(s)
- Junye Liu
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Lulu Xia
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Shilei Wang
- Department of Dermatology and Cosmetology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Xuefei Cai
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China
| | - Xiaoli Wu
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Chunhong Zou
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Baoju Shan
- Pediatric Research Institute; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child development and Critical Disorders; Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Miao Luo
- College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.,Department of Clinical Laboratory, Yubei District People's Hospital, Chongqing, China
| | - Deqiang Wang
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.,College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
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41
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Direct Regulation of DNA Repair by E2F and RB in Mammals and Plants: Core Function or Convergent Evolution? Cancers (Basel) 2021; 13:cancers13050934. [PMID: 33668093 PMCID: PMC7956360 DOI: 10.3390/cancers13050934] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/10/2021] [Accepted: 02/19/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Retinoblastoma (RB) proteins and E2F transcription factors partner together to regulate the cell cycle in many eukaryotic organisms. In organisms that lack one or both of these proteins, other proteins have taken on the essential function of cell cycle regulation. RB and E2F also have important functions outside of the cell cycle, including DNA repair. This review summarizes the non-canonical functions of RB and E2F in maintaining genome integrity and raises the question of whether such functions have always been present or have evolved more recently. Abstract Members of the E2F transcription factor family regulate the expression of genes important for DNA replication and mitotic cell division in most eukaryotes. Homologs of the retinoblastoma (RB) tumor suppressor inhibit the activity of E2F factors, thus controlling cell cycle progression. Organisms such as budding and fission yeast have lost genes encoding E2F and RB, but have gained genes encoding other proteins that take on E2F and RB cell cycle-related functions. In addition to regulating cell proliferation, E2F and RB homologs have non-canonical functions outside the mitotic cell cycle in a variety of eukaryotes. For example, in both mammals and plants, E2F and RB homologs localize to DNA double-strand breaks (DSBs) and directly promote repair by homologous recombination (HR). Here, we discuss the parallels between mammalian E2F1 and RB and their Arabidopsis homologs, E2FA and RB-related (RBR), with respect to their recruitment to sites of DNA damage and how they help recruit repair factors important for DNA end resection. We also explore the question of whether this role in DNA repair is a conserved ancient function of the E2F and RB homologs in the last eukaryotic common ancestor or whether this function evolved independently in mammals and plants.
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Wilkinson PD, Duncan AW. Differential Roles for Diploid and Polyploid Hepatocytes in Acute and Chronic Liver Injury. Semin Liver Dis 2021; 41:42-49. [PMID: 33764484 PMCID: PMC8056861 DOI: 10.1055/s-0040-1719175] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocytes are the primary functional cells of the liver that perform essential roles in homeostasis, regeneration, and injury. Most mammalian somatic cells are diploid and contain pairs of each chromosome, but there are also polyploid cells containing additional sets of chromosomes. Hepatocytes are among the best described polyploid cells, with polyploids comprising more than 25 and 90% of the hepatocyte population in humans and mice, respectively. Cellular and molecular mechanisms that regulate hepatic polyploidy have been uncovered, and in recent years, diploid and polyploid hepatocytes have been shown to perform specialized functions. Diploid hepatocytes accelerate liver regeneration induced by resection and may accelerate compensatory regeneration after acute injury. Polyploid hepatocytes protect the liver from tumor initiation in hepatocellular carcinoma and promote adaptation to tyrosinemia-induced chronic injury. This review describes how ploidy variations influence cellular activity and presents a model for context-specific functions for diploid and polyploid hepatocytes.
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Affiliation(s)
- Patrick D Wilkinson
- Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Andrew W Duncan
- Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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Sladky VC, Knapp K, Szabo TG, Braun VZ, Bongiovanni L, van den Bos H, Spierings DCJ, Westendorp B, Curinha A, Stojakovic T, Scharnagl H, Timelthaler G, Tsuchia K, Pinter M, Semmler G, Foijer F, de Bruin A, Reiberger T, Rohr‐Udilova N, Villunger A. PIDDosome-induced p53-dependent ploidy restriction facilitates hepatocarcinogenesis. EMBO Rep 2020; 21:e50893. [PMID: 33225610 PMCID: PMC7726793 DOI: 10.15252/embr.202050893] [Citation(s) in RCA: 30] [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: 05/13/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/12/2022] Open
Abstract
Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. This multi-protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome-induced p53-activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro-tumorigenic effect of PIDDosome-mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts poor survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and that tumor cell density may serve as a novel prognostic marker for recurrence-free survival in HCC patients.
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Affiliation(s)
- Valentina C Sladky
- Institute of Developmental ImmunologyBiocenterMedical University of InnsbruckInnsbruckAustria
| | - Katja Knapp
- Institute of Developmental ImmunologyBiocenterMedical University of InnsbruckInnsbruckAustria
| | - Tamas G Szabo
- Institute of Developmental ImmunologyBiocenterMedical University of InnsbruckInnsbruckAustria
| | - Vincent Z Braun
- Institute of Developmental ImmunologyBiocenterMedical University of InnsbruckInnsbruckAustria
| | - Laura Bongiovanni
- Department of Biomolecular Health SciencesFaculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Hilda van den Bos
- European Research Institute for the Biology of AgeingUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Diana CJ Spierings
- European Research Institute for the Biology of AgeingUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Bart Westendorp
- Department of Biomolecular Health SciencesFaculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Ana Curinha
- Institute of PathophysiologyBiocenterMedical University of InnsbruckInnsbruckAustria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory DiagnosticsUniversity Hospital GrazGrazAustria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory DiagnosticsMedical University of GrazGrazAustria
| | - Gerald Timelthaler
- Institute for Cancer ResearchInternal Medicine IMedical University of ViennaViennaAustria
| | - Kaoru Tsuchia
- Department of Gastroenterology & HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Matthias Pinter
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
| | - Georg Semmler
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
| | - Floris Foijer
- European Research Institute for the Biology of AgeingUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Alain de Bruin
- Department of Biomolecular Health SciencesFaculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
- Department PediatricsUniversity Medical Center GroningenUniversity GroningenGroningenThe Netherlands
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI‐RUD)ViennaAustria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| | - Nataliya Rohr‐Udilova
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
| | - Andreas Villunger
- Institute of Developmental ImmunologyBiocenterMedical University of InnsbruckInnsbruckAustria
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI‐RUD)ViennaAustria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
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Excessive E2F Transcription in Single Cancer Cells Precludes Transient Cell-Cycle Exit after DNA Damage. Cell Rep 2020; 33:108449. [PMID: 33264622 DOI: 10.1016/j.celrep.2020.108449] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 08/26/2020] [Accepted: 11/09/2020] [Indexed: 12/29/2022] Open
Abstract
E2F transcription factors control the expression of cell-cycle genes. Cancers often demonstrate enhanced E2F target gene expression, which can be explained by increased percentages of replicating cells. However, we demonstrate in human cancer biopsy specimens that individual neoplastic cells display abnormally high levels of E2F-dependent transcription. To mimic this situation, we delete the atypical E2F repressors (E2F7/8) or overexpress the E2F3 activator in untransformed cells. Cells with elevated E2F activity during S/G2 phase fail to exit the cell cycle after DNA damage and undergo mitosis. In contrast, wild-type cells complete S phase and then exit the cell cycle by activating the APC/CCdh1 via repression of the E2F target Emi1. Many arrested wild-type cells eventually inactivate APC/CCdh1 to execute a second round of DNA replication and mitosis, thereby becoming tetraploid. Cells with elevated E2F transcription fail to exit the cell cycle after DNA damage, which potentially causes genomic instability, promotes malignant progression, and reduces drug sensitivity.
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Dewhurst MR, Ow JR, Zafer G, van Hul NKM, Wollmann H, Bisteau X, Brough D, Choi H, Kaldis P. Loss of hepatocyte cell division leads to liver inflammation and fibrosis. PLoS Genet 2020; 16:e1009084. [PMID: 33147210 PMCID: PMC7641358 DOI: 10.1371/journal.pgen.1009084] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022] Open
Abstract
The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. Here, we investigate whether blocking hepatocyte division using two different mouse models affects physiology as well as clinical liver manifestations like fibrosis and inflammation. We find that in P14 Cdk1Liv-/- mice, where the division of hepatocytes is abolished, polyploidy, DNA damage, and increased p53 signaling are prevalent. Cdk1Liv-/- mice display classical markers of liver damage two weeks after birth, including elevated ALT, ALP, and bilirubin levels, despite the lack of exogenous liver injury. Inflammation was further studied using cytokine arrays, unveiling elevated levels of CCL2, TIMP1, CXCL10, and IL1-Rn in Cdk1Liv-/- liver, which resulted in increased numbers of monocytes. Ablation of CDK2-dependent DNA re-replication and polyploidy in Cdk1Liv-/- mice reversed most of these phenotypes. Overall, our data indicate that blocking hepatocyte division induces biological processes driving the onset of the disease phenotype. It suggests that the decrease in hepatocyte division observed in liver disease may not only be a consequence of fibrosis and inflammation, but also a pathological cue.
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Affiliation(s)
- Matthew R. Dewhurst
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
- Lydia Becker Institute of Immunology and Inflammation; and Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Jin Rong Ow
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
| | - Gözde Zafer
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
- Department of Biochemistry, National University of Singapore (NUS), Singapore
| | - Noémi K. M. van Hul
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
| | - Heike Wollmann
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
| | - Xavier Bisteau
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
| | - David Brough
- Lydia Becker Institute of Immunology and Inflammation; and Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Hyungwon Choi
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Philipp Kaldis
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
- Department of Biochemistry, National University of Singapore (NUS), Singapore
- Department of Clinical Sciences, Lund University, Clinical Research Centre (CRC), Sweden
- * E-mail:
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Gemble S, Basto R. CHRONOCRISIS: When Cell Cycle Asynchrony Generates DNA Damage in Polyploid Cells. Bioessays 2020; 42:e2000105. [PMID: 32885500 DOI: 10.1002/bies.202000105] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/19/2020] [Indexed: 12/16/2022]
Abstract
Polyploid cells contain multiple copies of all chromosomes. Polyploidization can be developmentally programmed to sustain tissue barrier function or to increase metabolic potential and cell size. Programmed polyploidy is normally associated with terminal differentiation and poor proliferation capacity. Conversely, non-programmed polyploidy can give rise to cells that retain the ability to proliferate. This can fuel rapid genome rearrangements and lead to diseases like cancer. Here, the mechanisms that generate polyploidy are reviewed and the possible challenges upon polyploid cell division are discussed. The discussion is framed around a recent study showing that asynchronous cell cycle progression (an event that is named "chronocrisis") of different nuclei from a polyploid cell can generate DNA damage at mitotic entry. The potential mechanisms explaining how mitosis in non-programmed polyploid cells can generate abnormal karyotypes and genetic instability are highlighted.
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Affiliation(s)
- Simon Gemble
- Biology of Centrosomes and Genetic Instability Lab, Institut Curie, PSL Research University, CNRS UMR144, 12 rue Lhomond, Paris, 75005, France
| | - Renata Basto
- Biology of Centrosomes and Genetic Instability Lab, Institut Curie, PSL Research University, CNRS UMR144, 12 rue Lhomond, Paris, 75005, France
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Abstract
Polyploidy (or whole-genome duplication) is the condition of having more than two basic sets of chromosomes. Polyploidization is well tolerated in many species and can lead to specific biological functions. In mammals, programmed polyploidization takes place during development in certain tissues, such as the heart and placenta, and is considered a feature of differentiation. However, unscheduled polyploidization can cause genomic instability and has been observed in pathological conditions, such as cancer. Polyploidy of the liver parenchyma was first described more than 100 years ago. The liver is one of the few mammalian organs that display changes in polyploidy during homeostasis, regeneration and in response to damage. In the human liver, approximately 30% of hepatocytes are polyploid. The polyploidy of hepatocytes results from both nuclear polyploidy (an increase in the amount of DNA per nucleus) and cellular polyploidy (an increase in the number of nuclei per cell). In this Review, we discuss the regulation of polyploidy in liver development and pathophysiology. We also provide an overview of current knowledge about the mechanisms of hepatocyte polyploidization, its biological importance and the fate of polyploid hepatocytes during liver tumorigenesis.
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Zybina TG, Zybina EV. Role of cell cycling and polyploidy in placental trophoblast of different mammalian species. Reprod Domest Anim 2020; 55:895-904. [DOI: 10.1111/rda.13732] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 05/07/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Tatiana G. Zybina
- Laboratory of Cell Morphology Institute of Cytology RAS St.‐Petersburg Russia
| | - Eugenia V. Zybina
- Laboratory of Cell Morphology Institute of Cytology RAS St.‐Petersburg Russia
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Sladky VC, Villunger A. Uncovering the PIDDosome and caspase-2 as regulators of organogenesis and cellular differentiation. Cell Death Differ 2020; 27:2037-2047. [PMID: 32415279 PMCID: PMC7308375 DOI: 10.1038/s41418-020-0556-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/24/2020] [Accepted: 04/28/2020] [Indexed: 02/08/2023] Open
Abstract
The PIDDosome is a multiprotein complex that drives activation of caspase-2, an endopeptidase originally implicated in apoptosis. Yet, unlike other caspases involved in cell death and inflammation, caspase-2 seems to exert additional versatile functions unrelated to cell death. These emerging roles range from control of transcription factor activity to ploidy surveillance. Thus, caspase-2 and the PIDDosome act as a critical regulatory unit controlling cellular differentiation processes during organogenesis and regeneration. These newly established functions of the PIDDosome and its downstream effector render its components attractive targets for drug-development aiming to prevent fatty liver diseases, neurodegenerative disorders or osteoporosis. ![]()
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Affiliation(s)
- Valentina C Sladky
- Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Andreas Villunger
- Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria. .,Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, 1090, Vienna, Austria. .,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria.
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Lin YH, Zhang S, Zhu M, Lu T, Chen K, Wen Z, Wang S, Xiao G, Luo D, Jia Y, Li L, MacConmara M, Hoshida Y, Singal A, Yopp A, Wang T, Zhu H. Mice With Increased Numbers of Polyploid Hepatocytes Maintain Regenerative Capacity But Develop Fewer Hepatocellular Carcinomas Following Chronic Liver Injury. Gastroenterology 2020; 158:1698-1712.e14. [PMID: 31972235 PMCID: PMC8902703 DOI: 10.1053/j.gastro.2020.01.026] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 12/24/2019] [Accepted: 01/02/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Thirty to 90% of hepatocytes contain whole-genome duplications, but little is known about the fates or functions of these polyploid cells or how they affect development of liver disease. We investigated the effects of continuous proliferative pressure, observed in chronically damaged liver tissues, on polyploid cells. METHODS We studied Rosa-rtTa mice (controls) and Rosa-rtTa;TRE-short hairpin RNA mice, which have reversible knockdown of anillin, actin binding protein (ANLN). Transient administration of doxycycline increases the frequency and degree of hepatocyte polyploidy without permanently altering levels of ANLN. Mice were then given diethylnitrosamine and carbon tetrachloride (CCl4) to induce mutations, chronic liver damage, and carcinogenesis. We performed partial hepatectomies to test liver regeneration and then RNA-sequencing to identify changes in gene expression. Lineage tracing was used to rule out repopulation from non-hepatocyte sources. We imaged dividing hepatocytes to estimate the frequency of mitotic errors during regeneration. We also performed whole-exome sequencing of 54 liver nodules from patients with cirrhosis to quantify aneuploidy, a possible outcome of polyploid cell divisions. RESULTS Liver tissues from control mice given CCl4 had significant increases in ploidy compared with livers from uninjured mice. Mice with knockdown of ANLN had hepatocyte ploidy above physiologic levels and developed significantly fewer liver tumors after administration of diethylnitrosamine and CCl4 compared with control mice. Increased hepatocyte polyploidy was not associated with altered regenerative capacity or tissue fitness, changes in gene expression, or more mitotic errors. Based on lineage-tracing experiments, non-hepatocytes did not contribute to liver regeneration in mice with increased polyploidy. Despite an equivalent rate of mitosis in hepatocytes of differing ploidies, we found no lagging chromosomes or micronuclei in mitotic polyploid cells. In nodules of human cirrhotic liver tissue, there was no evidence of chromosome-level copy number variations. CONCLUSIONS Mice with increased polyploid hepatocytes develop fewer liver tumors following chronic liver damage. Remarkably, polyploid hepatocytes maintain the ability to regenerate liver tissues during chronic damage without generating mitotic errors, and aneuploidy is not commonly observed in cirrhotic livers. Strategies to increase numbers of polypoid hepatocytes might be effective in preventing liver cancer.
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Affiliation(s)
- Yu-Hsuan Lin
- Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine
| | - Shuyuan Zhang
- Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine
| | - Min Zhu
- Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine
| | - Tianshi Lu
- Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine,Quantitative Biomedical Research Center, Department of Population and Data Sciences
| | - Kenian Chen
- Quantitative Biomedical Research Center, Department of Population and Data Sciences
| | - Zhuoyu Wen
- Quantitative Biomedical Research Center, Department of Population and Data Sciences
| | - Shidan Wang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences
| | - Guanghua Xiao
- Quantitative Biomedical Research Center, Department of Population and Data Sciences
| | - Danni Luo
- Quantitative Biomedical Research Center, Department of Population and Data Sciences
| | - Yuemeng Jia
- Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine
| | - Lin Li
- Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine
| | | | | | | | | | - Tao Wang
- Quantitative Biomedical Research Center, Department of Population and Data Sciences,Kidney Cancer Program, Simmons Comprehensive Cancer Center,Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Hao Zhu
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
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