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Cited by 61Liver physiology and pathologyEpigenetics and DNA MethylationTissue Engineering and Regenerative Medicine

DNMT1 is a required genomic regulator for murine liver histogenesis and regeneration

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Kaji, Kosuke, Factor, Valentina M., Andersen, Jesper B., Durkin, Marian E., Tomokuni, Akira, Marquardt, Jens U., Matter, Matthias S., Hoang, Tanya +2 more·2016·Hepatology
DOI 10.1002/hep.28563PMC PMC5841553
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Abstract

DNA methyltransferase 1 (DNMT1) is an essential regulator maintaining both epigenetic reprogramming during DNA replication and genome stability. We investigated the role of DNMT1 in the regulation of postnatal liver histogenesis under homeostasis and stress conditions. We generated Dnmt1 conditional knockout mice (Dnmt1Δalb ) by crossing Dnmt1fl/fl with albumin‐cyclization recombination transgenic mice. Serum, liver tissues, and primary hepatocytes were collected from 1‐week‐old to 20‐week old mice. The Dnmt1Δalb phenotype was assessed by histology, confocal and electron microscopy, biochemistry, as well as transcriptome and methylation profiling. Regenerative growth was induced by partial hepatectomy and exposure to carbon tetrachloride. The impact of Dnmt1 knockdown was also analyzed in hepatic progenitor cell lines; proliferation, apoptosis, DNA damage, and sphere formation were assessed. Dnmt1 loss in postnatal hepatocytes caused global hypomethylation, enhanced DNA damage response, and initiated a senescence state causing a progressive inability to maintain tissue homeostasis and proliferate in response to injury. The liver regenerated through activation and repopulation from progenitors due to lineage‐dependent differences in albumin‐cyclization recombination expression, providing a basis for selection of less mature and therefore less damaged hepatic progenitor cell progeny. Consistently, efficient knockdown of Dnmt1 in cultured hepatic progenitor cells caused severe DNA damage, cell cycle arrest, senescence, and cell death. Mx1‐cyclization recombination‐driven deletion of Dnmt1 in adult quiescent hepatocytes did not affect liver homeostasis. Conclusion: These results establish the indispensable role of DNMT1‐mediated epigenetic regulation in postnatal liver growth and regeneration; Dnmt1Δalb mice provide a unique experimental model to study the role of senescence and the contribution of progenitor cells to physiological and regenerative liver growth. (H epatology 2016;64:582‐598)

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  • Dnmt1 deletion was accompanied by loss of the perivenous enzyme CYP2E1, causing unresponsiveness to CCl4.

    “Intriguingly, deletion of Dnmt1 was accompanied by the loss of the perivenous enzyme cytochrome CYP2E1, which is responsible for the bioactivation of carbon tetrachloride (CCl4), thus causing unresponsiveness to this drug.96”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [96]

    The Results section (“Differentiation Defects in Postnatal Hepatocytes Caused by Dnmt1 Deletion”; page not provided) reports that Dnmt1-deleted mice resisted CCl4 liver injury during their first eight postnatal weeks, alongside strong repression of CYP2E1, the major enzyme responsible for CCl4 bioactivation. It describes the findings as coincident, not as proof that CYP2E1 loss caused complete unresponsiveness; the claim also omits the age limit. (LLM, conf=0.86)

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  • Dnmt1 deletion was accompanied by liver fibrosis and inflammation, and a reduced hepatocyte proliferative capacity in response to injury.

    “This was accompanied by liver fibrosis and inflammation, and a reduced hepatocyte proliferative capacity in response to injury.”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [96]

  • Deletion of Dnmt1 in postnatal hepatocytes using Alb-Cre transgenic mice caused global hypomethylation, enhanced the DNA damage response, and induced a senescent state.

    “deletion of Dnmt1 in postnatal hepatocytes using Alb-Cre transgenic mice caused global hypomethylation, enhanced the DNA damage response, and induced a senescent state.”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [96]

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Research works printed but not linked: 41

  1. [1]Li E Zhang Y DNA methylation in mammals Cold Spring Harb Perspect Biol 2014 6 a019133 24789823 PMC3996472
  2. [2]Song J Teplova M Ishibe-Murakami S Patel DJ Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation Science 2012 335 709 712 22323818 PMC4693633
  3. [3]Jeltsch A Jurkowska RZ New concepts in DNA methylation Trends Biochem Sci 2014 39 310 318 24947342
  4. [4]Walsh CP Chaillet JR Bestor TH Transcription of IAP endogenous retroviruses is constrained by cytosine methylation Nat Genet 1998 20 116 117 9771701
  5. [5]Jackson-Grusby L Beard C Possemato R Tudor M Fambrough D Csankovszki G Dausman J Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation Nat Genet 2001 27 31 39 11137995
  6. [6]Takebayashi S Tamura T Matsuoka C Okano M Major and essential role for the DNA methylation mark in mouse embryogenesis and stable association of DNMT1 with newly replicated regions Mol Cell Biol 2007 27 8243 8258 17893328 PMC2169176
  7. [7]Georgia S Kanji M Bhushan A DNMT1 represses p53 to maintain progenitor cell survival during pancreatic organogenesis Genes Dev 2013 27 372 377 23431054 PMC3589554
  8. [8]Elliott EN Sheaffer KL Schug J Stappenbeck TS Kaestner KH Dnmt1 is essential to maintain progenitors in the perinatal intestinal epithelium Development 2015 142 2163 2172 26023099 PMC4483766
  9. [9]Trowbridge JJ Snow JW Kim J Orkin SH DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells Cell Stem Cell 2009 5 442 449 19796624 PMC2767228
  10. [10]Sen GL Reuter JA Webster DE Zhu L Khavari PA DNMT1 maintains progenitor function in self-renewing somatic tissue Nature 2010 463 563 567 20081831 PMC3050546
  11. [11]Fan G Martinowich K Chin MH He F Fouse SD Hutnick L Hattori D DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling Development 2005 132 3345 3356 16014513
  12. [12]Snykers S Henkens T De Rop E Vinken M Fraczek J De Kock J De Prins E Role of epigenetics in liver-specific gene transcription, hepatocyte differentiation and stem cell reprogrammation J Hepatol 2009 51 187 211 19457566
  13. [13]Lu H Cui JY Gunewardena S Yoo B Zhong XB Klaassen CD Hepatic ontogeny and tissue distribution of mRNAs of epigenetic modifiers in mice using RNA-sequencing Epigenetics 2012 7 914 929 22772165 PMC3427287
  14. [14]Gailhouste L Gomez-Santos L Hagiwara K Hatada I Kitagawa N Kawaharada K Thirion M miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cells Hepatology 2013 58 1153 1165 23532995
  15. [15]Waterland RA Kellermayer R Rached MT Tatevian N Gomes MV Zhang J Zhang L Epigenomic profiling indicates a role for DNA methylation in early postnatal liver development Hum Mol Genet 2009 18 3026 3038 19457928 PMC2714727
  16. [16]Acevedo LG Bieda M Green R Farnham PJ Analysis of the mechanisms mediating tumor-specific changes in gene expression in human liver tumors Cancer Res 2008 68 2641 2651 18413731 PMC2567918
  17. [18]Roos WP Kaina B DNA damage-induced cell death by apoptosis Trends Mol Med 2006 12 440 450 16899408
  18. [20]Georgakopoulou EA Tsimaratou K Evangelou K Fernandez Marcos PJ Zoumpourlis V Trougakos IP Kletsas D Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues Aging (Albany NY) 2013 5 37 50 23449538 PMC3616230
  19. [21]Munoz-Espin D Serrano M Cellular senescence: from physiology to pathology Nat Rev Mol Cell Biol 2014 15 482 496 24954210
  20. [22]Singh K Matsuyama S Drazba JA Almasan A Autophagy-dependent senescence in response to DNA damage and chronic apoptotic stress Autophagy 2012 8 236 251 22240589 PMC3336077
  21. [23]Wong FW Chan WY Lee SS Resistance to carbon tetrachloride-induced hepatotoxicity in mice which lack CYP2E1 expression Toxicol Appl Pharmacol 1998 153 109 118 9875305
  22. [24]Berasain C Avila MA Deciphering liver zonation: new insights into the beta-catenin, Tcf4, and HNF4alpha triad Hepatology 2014 59 2080 2082 24407883
  23. [25]Hailfinger S Jaworski M Braeuning A Buchmann A Schwarz M Zonal gene expression in murine liver: lessons from tumors Hepatology 2006 43 407 414 16496347
  24. [26]Wei P Zhang J Egan-Hafley M Liang S Moore DD The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism Nature 2000 407 920 923 11057673
  25. [27]Chen WD Fu X Dong B Wang YD Shiah S Moore DD Huang W Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver Hepatology 2012 56 1499 1509 22488010 PMC3407349
  26. [28]Williams MJ Clouston AD Forbes SJ Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion Gastroenterology 2014 146 349 356 24315991
  27. [29]Factor VM Radaeva SA Thorgeirsson SS Origin and fate of oval cells in dipin-induced hepatocarcinogenesis in the mouse Am J Pathol 1994 145 409 422 8053498 PMC1887389
  28. [30]Lu WY Bird TG Boulter L Tsuchiya A Cole AM Hay T Guest RV Hepatic progenitor cells of biliary origin with liver repopulation capacity Nat Cell Biol 2015 17 971 983 26192438 PMC4612439
  29. [31]Espanol-Suner R Carpentier R Van Hul N Legry V Achouri Y Cordi S Jacquemin P Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice Gastroenterology 2012 143 1564 1575 e1567 22922013
  30. [32]Nikolaou KC Moulos P Chalepakis G Hatzis P Oda H Reinberg D Talianidis I Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR-SET7-deficient livers EMBO J 2015 34 430 447 25515659 PMC4330999
  31. [33]Forbes SJ Rosenthal N Preparing the ground for tissue regeneration: from mechanism to therapy Nat Med 2014 20 857 869 25100531
  32. [34]Novikoff PM Yam A Stem cells and rat liver carcinogenesis: contributions of confocal and electron microscopy J Histochem Cytochem 1998 46 613 626 9562570
  33. [35]Isse K Lesniak A Grama K Maier J Specht S Castillo-Rama M Lunz J Preexisting epithelial diversity in normal human livers: a tissue-tethered cytometric analysis in portal/periportal epithelial cells Hepatology 2013 57 1632 1643 23150208 PMC3612393
  34. [36]Nagahama Y Sone M Chen X Okada Y Yamamoto M Xin B Matsuo Y Contributions of hepatocytes and bile ductular cells in ductular reactions and remodeling of the biliary system after chronic liver injury Am J Pathol 2014 184 3001 3012 25193593
  35. [37]Vire E Brenner C Deplus R Blanchon L Fraga M Didelot C Morey L The Polycomb group protein EZH2 directly controls DNA methylation Nature 2006 439 871 874 16357870
  36. [39]Brown KD Robertson KD DNMT1 knockout delivers a strong blow to genome stability and cell viability Nat Genet 2007 39 289 290 17325677
  37. [40]Chen T Hevi S Gay F Tsujimoto N He T Zhang B Ueda Y Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells Nat Genet 2007 39 391 396 17322882
  38. [41]Campbell S Ismail IH Young LC Poirier GG Hendzel MJ Polycomb repressive complex 2 contributes to DNA double-strand break repair Cell Cycle 2013 12 2675 2683 23907130 PMC3865057
  39. [43]Iverson SV Comstock KM Kundert JA Schmidt EE Contributions of new hepatocyte lineages to liver growth, maintenance, and regeneration in mice Hepatology 2011 54 655 663 21538442 PMC3145049
  40. [44]Yanger K Knigin D Zong Y Maggs L Gu G Akiyama H Pikarsky E Adult hepatocytes are generated by self-duplication rather than stem cell differentiation Cell Stem Cell 2014 15 340 349 25130492 PMC4505916
  41. [45]Jors S Jeliazkova P Ringelhan M Thalhammer J Durl S Ferrer J Sander M Lineage fate of ductular reactions in liver injury and carcinogenesis J Clin Invest 2015 125 2445 2457 25915586 PMC4497753

Cited by

Sorted by citations

Authors
Kaji, K., Factor, V. M., Andersen, J. B., Durkin, M. E., Tomokuni, A., Marquardt, J. U., Matter, M. S., Hoang, T., Conner, E. A., & Thorgeirsson, S. S.
Affiliations
  • National Institutes of Health (US)
  • University of Copenhagen (DK)
Corresponding author
Thorgeirsson, Snorri S.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2016-04-28
Volume
64
Issue
2
Pages
582-598
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.28563
PMC
PMC5841553
OpenAlex
W2306368743
Cited by
61
References
4
Citations by year
2026: 2 · 2025: 3 · 2024: 10 · 2023: 6 · 2022: 9 · 2021: 6 · 2020: 7 · 2019: 8 · 2018: 4 · 2017: 3 · 2016: 3
FWCI
4.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • Volkswagen Foundation
  • Deutsche Krebshilfe (DKH 110989)
  • Novo Nordisk Fonden (NNF15OC0014040)
  • National Institutes of Health
  • National Cancer Institute (Z01BC005453)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
DNMT1, DNA methylation, liver regeneration, hepatic progenitor cells, DNA damage response, cellular senescence, global DNA hypomethylation, partial hepatectomy, carbon tetrachloride, epigenetic regulation, hepatocyte proliferation, conditional knockout mice
MeSH terms
DNA (Cytosine-5-)-Methyltransferase 1, Animals, Cell Differentiation, DNA (Cytosine-5-)-Methyltransferases, DNA Damage, Liver, Liver Regeneration, Male, Mice, Transgenic, Stem Cells, Cellular Senescence, Hepatocytes, Genomic Instability, Epigenesis, Genetic

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