Epigenetic Compensation Promotes Liver Regeneration

Shuang Wang, Chi Zhang, Dan Hasson, Anal Desai, Sucharita SenBanerjee, Elena Magnani, Chinweike Ukomadu, Amaia Lujambio, Emily Bernstein, Kirsten C. Sadler

Research output: Contribution to journalArticlepeer-review

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. It is not clear how complex epigenetic functions are coordinated to both regulate gene expression and mitigate transposon threat. Wang et al. discovered that to compensate for loss of DNA methylation-mediated transposon silencing, another repressive epigenetic mark is diverted from proregenerative genes, resulting in enhanced liver regeneration.

Original languageEnglish (US)
Pages (from-to)43-56.e6
JournalDevelopmental Cell
Volume50
Issue number1
DOIs
StatePublished - Jul 1 2019

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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