Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration
Open accessAbstract
Mammals have partially lost the extensive regenerative capabilities of some vertebrates, possibly as a result of chromatin-remodeling mechanisms that enforce terminal differentiation. Here, we show that deleting the SWI/SNF component Arid1a substantially improves mammalian regeneration. Arid1a expression is suppressed in regenerating tissues, and genetic deletion of Arid1a increases tissue repair following an array of injuries. Arid1a deficiency in the liver increases proliferation, reduces tissue damage and fibrosis, and improves organ function following surgical resection and chemical injuries. Hepatocyte-specific deletion is also sufficient to increase proliferation and regeneration without excessive overgrowth, and global Arid1a disruption potentiates soft tissue healing in the ear. We show that Arid1a loss reprograms chromatin to restrict promoter access by transcription factors such as C/ebpα, which enforces differentiation, and E2F4, which suppresses cell-cycle re-entry. Thus, epigenetic reprogramming mediated by deletion of a single gene improves mammalian regeneration and suggests strategies to promote tissue repair after injury.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ARID1A, a component of the SWI/SNF chromatin remodelling complex, suppresses hepatocyte proliferation and regeneration by limiting access of transcription factors to their target genes.
“For instance, ARID1A, a component of the SWI/SNF (SWItch/sucrose non-fermentable) chromatin remodelling complex, has been shown to suppress hepatocyte proliferation and regeneration by limiting access of transcription factors to their target genes. These include C/EBPα, HNF4α, and E2F, all of which are known to be involved in regulating zonated gene expression.62”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [62]
The Results section (‘Loss of Arid1a increases post-injury proliferation by restraining repressive E2Fs’) says Arid1a–SWI/SNF normally promotes transcription-factor access. The Discussion says loss of Arid1a restricts that access and improves regeneration. Thus the source supports ARID1A as a regeneration suppressor, but says the opposite of the claimed mechanism. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Rejuvenation of aged progenitor cells by exposure to a young systemic environment
Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005) · Nature · doi:10.1038/nature03260 · Cited by 2,287 · see citing works
Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle
Sinha, M., Jang, Y. C., Oh, J., Khong, D., Wu, E. Y., Manohar, R., Miller, C., Regalado, S. G., Loffredo, F. S., Pancoast, J. R., et al. (2014) · Science · doi:10.1126/science.1251152 · Cited by 824 · see citing works
Flagged first, then by citations
Research works printed but not linked: 45
- Beer S Komatsubara K Bellovin DI Kurobe M Sylvester K Felsher DW 2008 Hepatotoxin-induced changes in the adult murine liver promote MYC-induced tumorigenesis PloS one 3 e2493 18560566 PMC2423614
- Bucher NL Swaffield MN Ditroia JF 1964 The Influence of Age Upon the Incorporation of Thymidine-2-C14 into the DNA of Regenerating Rat Liver Cancer research 24 509 512 14147827
- Chan-On W Nairismagi ML Ong CK Lim WK Dima S Pairojkul C Lim KH McPherson JR Cutcutache I Heng HL 2013 Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers Nature genetics 45 1474 1478 24185513
- Chandler RL Brennan J Schisler JC Serber D Patterson C Magnuson T 2013 ARID1a-DNA interactions are required for promoter occupancy by SWI/SNF Molecular and cellular biology 33 265 280 23129809 PMC3554127
- Chandler RL Damrauer JS Raab JR Schisler JC Wilkerson MD Didion JP Starmer J Serber D Yee D Xiong J 2015 Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling Nature communications 6 6118 PMC4308813 25625625
- Dykhuizen EC Hargreaves DC Miller EL Cui K Korshunov A Kool M Pfister S Cho YJ Zhao K Crabtree GR 2013 BAF complexes facilitate decatenation of DNA by topoisomerase IIalpha Nature 497 624 627 23698369 PMC3668793
- Fujimoto A Totoki Y Abe T Boroevich KA Hosoda F Nguyen HH Aoki M Hosono N Kubo M Miya F 2012 Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators Nature genetics 44 760 764 22634756
- Gao X Tate P Hu P Tjian R Skarnes WC Wang Z 2008 ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a Proceedings of the National Academy of Sciences of the United States of America 105 6656 6661 18448678 PMC2373334
- Guan B Rahmanto YS Wu RC Wang Y Wang Z Wang TL Shih Ie M 2014 Roles of deletion of Arid1a, a tumor suppressor, in mouse ovarian tumorigenesis Journal of the National Cancer Institute 106 PMC4056776 24899687
- Guichard C Amaddeo G Imbeaud S Ladeiro Y Pelletier L Maad IB Calderaro J Bioulac-Sage P Letexier M Degos F 2012 Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma Nature genetics 44 694 698 22561517 PMC3819251
- Hargreaves DC Crabtree GR 2011 ATP-dependent chromatin remodeling: genetics, genomics and mechanisms Cell research 21 396 420 21358755 PMC3110148
- Harris TE Albrecht JH Nakanishi M Darlington GJ 2001 CCAAT/enhancer-binding protein-alpha cooperates with p21 to inhibit cyclin-dependent kinase-2 activity and induces growth arrest independent of DNA binding The Journal of biological chemistry 276 29200 29209 11369759
- Heber-Katz E 1999 The regenerating mouse ear Seminars in cell & developmental biology 10 415 419 10497098
- Heinz S Benner C Spann N Bertolino E Lin YC Laslo P Cheng JX Murre C Singh H Glass CK 2010 Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities Molecular cell 38 576 589 20513432 PMC2898526
- Helming KC Wang X Wilson BG Vazquez F Haswell JR Manchester HE Kim Y Kryukov GV Ghandi M Aguirre AJ 2014 ARID1B is a specific vulnerability in ARID1A-mutant cancers Nature medicine 20 251 254 PMC3954704 24562383
- Huang J Deng Q Wang Q Li KY Dai JH Li N Zhu ZD Zhou B Liu XY Liu RF 2012 Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma Nature genetics 44 1117 1121 22922871
- Iakova P Awad SS Timchenko NA 2003 Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest Cell 113 495 506 12757710
- Inayoshi Y Miyake K Machida Y Kaneoka H Terajima M Dohda T Takahashi M Iijima S 2006 Mammalian chromatin remodeling complex SWI/SNF is essential for enhanced expression of the albumin gene during liver development Journal of biochemistry 139 177 188 16452305
- Jiao Y Pawlik TM Anders RA Selaru FM Streppel MM Lucas DJ Niknafs N Guthrie VB Maitra A Argani P 2013 Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas Nature genetics 45 1470 1473 24185509 PMC4013720
- Jin J Hong IH Lewis K Iakova P Breaux M Jiang Y Sullivan E Jawanmardi N Timchenko L Timchenko NA 2014 Cooperation of C/EBP family proteins and chromatin remodeling proteins is essential for termination of liver regeneration Hepatology PMC4280321 25043739
- Kadoch C Hargreaves DC Hodges C Elias L Ho L Ranish J Crabtree GR 2013 Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy Nature genetics 45 592 601 23644491 PMC3667980
- Langmead B Salzberg SL 2012 Fast gapped-read alignment with Bowtie 2 Nature methods 9 357 359 22388286 PMC3322381
- Lei I West J Yan Z Gao X Fang P Dennis JH Gnatovskiy L Wang W Kingston RE Wang Z 2015 BAF250a regulates nucleosome occupancy and histone modifications in priming embryonic stem cell differentiation The Journal of biological chemistry PMC4521052 26070559
- McBrearty BA Clark LD Zhang XM Blankenhorn EP Heber-Katz E 1998 Genetic analysis of a mammalian wound-healing trait Proceedings of the National Academy of Sciences of the United States of America 95 11792 11797 9751744 PMC21719
- Michalopoulos GK 2010 Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas The American journal of pathology 176 2 13 20019184 PMC2797862
- Mitchell C Willenbring H 2008 A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice Nature protocols 3 1167 1170 18600221
- Miyaoka Y Ebato K Kato H Arakawa S Shimizu S Miyajima A 2012 Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration Current biology: CB 22 1166 1175 22658593
- Mootha VK Lindgren CM Eriksson KF Subramanian A Sihag S Lehar J Puigserver P Carlsson E Ridderstrale M Laurila E 2003 PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes Nature genetics 34 267 273 12808457
- Nagl NG Jr Wang X Patsialou A Van Scoy M Moran E 2007 Distinct mammalian SWI/SNF chromatin remodeling complexes with opposing roles in cell-cycle control The EMBO journal 26 752 763 17255939 PMC1794396
- Onder TT Kara N Cherry A Sinha AU Zhu N Bernt KM Cahan P Marcarci BO Unternaehrer J Gupta PB 2012 Chromatin-modifying enzymes as modulators of reprogramming Nature 483 598 602 22388813 PMC3501145
- Pajcini KV Corbel SY Sage J Pomerantz JH Blau HM 2010 Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle Cell stem cell 7 198 213 20682446 PMC2919350
- Poss KD 2010 Advances in understanding tissue regenerative capacity and mechanisms in animals Nature reviews Genetics 11 710 722 PMC3069856 20838411
- Purushothaman S Saxena S Meghah V Swamy CV Ortega-Martinez O Dupont S Idris M 2015 Transcriptomic and proteomic analyses of Amphiura filiformis arm tissue-undergoing regeneration Journal of proteomics 112 113 124 25178173
- Ross-Innes CS Stark R Teschendorff AE Holmes KA Ali HR Dunning MJ Brown GD Gojis O Ellis IO Green AR 2012 Differential oestrogen receptor binding is associated with clinical outcome in breast cancer Nature 481 389 393 22217937 PMC3272464
- Schuppan D Afdhal NH 2008 Liver cirrhosis Lancet 371 838 851 18328931 PMC2271178
- Seifert AW Kiama SG Seifert MG Goheen JR Palmer TM Maden M 2012 Skin shedding and tissue regeneration in African spiny mice (Acomys) Nature 489 561 565 23018966 PMC3480082
- Shyh-Chang N Zhu H Yvanka de Soysa T Shinoda G Seligson MT Tsanov KM Nguyen L Asara JM Cantley LC Daley GQ 2013 Lin28 enhances tissue repair by reprogramming cellular metabolism Cell 155 778 792 24209617 PMC3917449
- Stadtfeld M Apostolou E Akutsu H Fukuda A Follett P Natesan S Kono T Shioda T Hochedlinger K 2010 Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells Nature 465 175 181 20418860 PMC3987905
- Tanaka EM Reddien PW 2011 The cellular basis for animal regeneration Developmental cell 21 172 185 21763617 PMC3139400
- Wang H Goode T Iakova P Albrecht JH Timchenko NA 2002 C/EBPalpha triggers proteasome-dependent degradation of cdk4 during growth arrest The EMBO journal 21 930 941 11867521 PMC125893
- Wang H Iakova P Wilde M Welm A Goode T Roesler WJ Timchenko NA 2001 C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4 Molecular cell 8 817 828 11684017
- Wu M Peng S Yang J Tu Z Cai X Cai CL Wang Z Zhao Y 2014 Baf250a orchestrates an epigenetic pathway to repress the Nkx2.5-directed contractile cardiomyocyte program in the sinoatrial node Cell research 24 1201 1213 25145359 PMC4185344
- Zhai Y Kuick R Tipton C Wu R Sessine M Wang Z Baker SJ Fearon ER Cho KR 2015 Arid1a inactivation in an Apc and Pten-defective mouse ovarian cancer model enhances epithelial differentiation and prolongs survival The Journal of pathology PMC4715504 26279473
- Zhang Y Liu T Meyer CA Eeckhoute J Johnson DS Bernstein BE Nusbaum C Myers RM Brown M Li W 2008 Model-based analysis of ChIP-Seq (MACS) Genome biology 9 R137 18798982 PMC2592715
- Zhu H Shah S Shyh-Chang N Shinoda G Einhorn WS Viswanathan SR Takeuchi A Grasemann C Rinn JL Lopez MF 2010 Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies Nature genetics 42 626 630 20512147 PMC3069638
Cited by
Sorted by citations
Liver homeostasis is maintained by midlobular zone 2 hepatocytes
Wei, Y., Wang, Y. G., Jia, Y., Li, L., Yoon, J., Zhang, S., Wang, Z., Zhang, Y., Zhu, M., Sharma, T., et al. (2021) · Science · doi:10.1126/science.abb1625 · Cited by 292 · see citing works
Self-citationLi, W., Yang, L., He, Q., Hu, C., Zhu, L., Ma, X., Ma, X., Bao, S., Li, L., Chen, Y., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.06.008 · Cited by 124 · see citing works
Self-citationGoldstein, I., Paakinaho, V., Baek, S., Sung, M.-H., & Hager, G. L. (2017) · Nature Communications · doi:10.1038/s41467-017-02055-5 · Cited by 97 · see citing works
SWI/SNF component <i>ARID1A</i> restrains pancreatic neoplasia formation
Wang, S. C., Nassour, I., Xiao, S., Zhang, S., Luo, X., Lee, J., Li, L., Sun, X., Nguyen, L. H., Chuang, J.-C., et al. (2019) · Gut · doi:10.1136/gutjnl-2017-315490 · Cited by 85 · see citing works
Self-citationA spatiotemporal atlas of mouse liver homeostasis and regeneration
Xu, J., Guo, P., Hao, S., Shangguan, S., Shi, Q., Volpe, G., Huang, K., Zuo, J., An, J., Yuan, Y., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01709-7 · Cited by 75 · see citing works
Self-citationJia, Y., Li, L., Lin, Y.-H., Gopal, P., Shen, S., Zhou, K., Yu, X., Sharma, T., Zhang, Y., Siegwart, D. J., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.01.001 · Cited by 59 · see citing works
Self-citationArid1a restrains Kras-dependent changes in acinar cell identity
Livshits, G., Alonso-Curbelo, D., Morris, J. P., Koche, R., Saborowski, M., Wilkinson, J. E., & Lowe, S. W. (2018) · eLife · doi:10.7554/elife.35216 · Cited by 48 · see citing works
Distinct hepatocyte identities in liver homeostasis and regeneration
Chen, F., Schönberger, K., & Tchorz, J. S. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100779 · Cited by 30 · see citing works
ATP-dependent chromatin remodelers in ageing and age-related disorders
Swer, P. B., & Sharma, R. (2021) · Biogerontology · doi:10.1007/s10522-020-09899-3 · Cited by 25 · see citing works
- Authors
- Sun, X., Chuang, J.-C., Kanchwala, M., Wu, L., Celen, C., Li, L., Liang, H., Zhang, S., Maples, T., Nguyen, L. H., Wang, S. C., Signer, R. A. J., Sorouri, M., Nassour, I., Liu, X., Xu, J., Wu, M., Zhao, Y., Kuo, Y.-C., Wang, Z., Xing, C., & Zhu, H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Sun Yat-sen University (CN)
- Howard Hughes Medical Institute (US)
- University of California San Diego (US)
- Icahn School of Medicine at Mount Sinai (US)
- University of Michigan (US)
- Corresponding author
- Zhu, Hao
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 18
- Issue
- 4
- Pages
- 456-466
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4826298
- OpenAlex
- W2309167097
- Cited by
- 161
- References
- 3
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 20 · 2023: 24 · 2022: 10 · 2021: 20 · 2020: 18 · 2019: 16 · 2018: 15 · 2017: 11 · 2016: 5
- FWCI
- 11.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- University of Pennsylvania
- University of Texas Southwestern Medical Center
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health (UL1TR001105)
- National Heart, Lung, and Blood Institute (K02HL103597, R01HL107376, R01HL109054)
- National Cancer Institute (R01CA190525, K08CA157727)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK093543)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- ARID1A, SWI/SNF complex, tissue regeneration, chromatin remodeling, epigenetic reprogramming, liver regeneration, hepatocyte proliferation, liver fibrosis, soft tissue healing, C/EBPα, E2F4, terminal differentiation, cell cycle re-entry
- MeSH terms
- Animals, Cell Differentiation, DNA-Binding Proteins, Liver, Liver Regeneration, Mice, Inbred C57BL, Mice, Transgenic, Nuclear Proteins, Transcription Factors, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
