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Dev Cell. 2019 Jul 1;50(1):43-56.e6. doi: 10.1016/j.devcel.2019.05.034. Epub 2019 Jun 20.

Epigenetic Compensation Promotes Liver Regeneration.

Author information

1
Department of Medicine/Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2
Program in Biology, New York University Abu Dhabi, Abu Dhabi, P.O. Box 129188, United Arab Emirates.
3
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
5
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; College of Arts and Sciences, Wentworth Institute of Technology, 504 Parker St., Boston, MA 02115, USA.
6
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, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
Department of Medicine/Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Program in Biology, New York University Abu Dhabi, Abu Dhabi, P.O. Box 129188, United Arab Emirates. Electronic address: kirsten.edepli@nyu.edu.

Abstract

Two major functions of the epigenome are to regulate gene expression and to suppress transposons. It is unclear how these functions are balanced during physiological challenges requiring tissue regeneration, where exquisite coordination of gene expression is essential. Transcriptomic analysis of seven time points following partial hepatectomy identified the epigenetic regulator UHRF1, which is essential for DNA methylation, as dynamically expressed during liver regeneration in mice. UHRF1 deletion in hepatocytes (Uhrf1HepKO) caused genome-wide DNA hypomethylation but, surprisingly, had no measurable effect on gene or transposon expression or liver homeostasis. Partial hepatectomy of Uhrf1HepKO livers resulted in early and sustained activation of proregenerative genes and enhanced liver regeneration. This was attributed to redistribution of H3K27me3 from promoters to transposons, effectively silencing them and, consequently, alleviating repression of liver regeneration genes, priming them for expression in Uhrf1HepKO livers. Thus, epigenetic compensation safeguards the genome against transposon activation, indirectly affecting gene regulation.

KEYWORDS:

DNA methylation; H3K27me3; UHRF1; epigenetic compensation; epigenomics; liver biology; partial hepatectomy; tissue regeneration; transposons

PMID:
31231040
PMCID:
PMC6615735
[Available on 2020-07-01]
DOI:
10.1016/j.devcel.2019.05.034

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