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The Epigenetic Balancing Act of Liver Regeneration

Review of “Epigenetic Compensation Promotes Liver Regeneration” from Developmental Cell by Stuart P. Atkinson

Researchers from the laboratory of Kirsten C. Sadler (Icahn School of Medicine at Mount Sinai, New York, USA/New York University Abu Dhabi, UAE) recently sought to understand the epigenomic “balancing act” that is liver tissue regeneration [1, 2]; just how does the epigenome orchestrate the induction of the gene expression programs required to activate regeneration in hepatocytes [3, 4] while repressing the numerous and potentially deleterious transposable elements present throughout the genome [5]?

To answer this intriguing epigenetic question, Wang et al. analyzed the transcriptomic and epigenetic changes associated with liver regeneration in the well-characterized mouse partial hepatectomy (PH) model [6, 7]. Fascinatingly, this new study now reveals that that repressive epigenetic modifications become diverted from proregenerative gene promoters to compensate for the loss of DNA methylation-mediated transposon silencing, resulting in enhanced liver regeneration [8].

Briefly, the authors discovered distinct patterns of gene expression during liver regeneration in mice, identified a group of epigenetic regulators displaying a similar temporal pattern as those genes controlling hepatocyte proliferation. This group included DNA methyltransferase 1 (DNMT1), although the authors focused on the dynamic expression of the UHRF1 (Ubiquitin Like with PHD and Ring Finger Domains 1) epigenetic regulator for further analysis. As would be expected for a gene essential for the maintenance of DNA methylation, the loss of UHRF1 in hepatocytes led to genome-wide DNA hypomethylation; however, this loss failed to elicit any alterations to gene expression, transposon expression, nor liver homeostasis.

While mice carrying hepatocytes lacking UHRF1 developed normally, partial hepatectomy prompted the early and robust upregulation of cell cycle genes, earlier hepatocyte proliferation, the early and sustained activation of proregenerative genes, and enhanced liver regeneration. Using chromatin immunoprecipitation sequencing analysis, the authors attributed these effects to the redistribution of a histone modification associated with gene repression (H3K27me3) from gene promoters of liver regeneration genes to transposons, thereby permitting the activation of said regeneration-associated genes while effectively silencing unwanted transcription from transposable elements.

While the discovery of this epigenetic balancing act during liver regeneration has prompted the authors to propose further experiments with drugs targeting epigenetic modulators as a potential means to induce epigenetic compensation in vivo to augment inherent liver regenerative capacity in models of liver disease and failure, they also highlight that their study provides yet more evidence for the lack of concordance between promoter DNA methylation and gene expression levels.

For more on how epigenetic balancing acts control liver regeneration, stay tuned to the Stem Cells Portal.

References

  1. Michalopoulos GK, Principles of liver regeneration and growth homeostasis. Comprehensive Physiology 2013;3:485-513.
  2. Miyaoka Y, Ebato K, Kato H, et al., Hypertrophy and Unconventional Cell Division of Hepatocytes Underlie Liver Regeneration. Current Biology 2012;22:1166-1175.
  3. Kang J, Hu J, Karra R, et al., Modulation of tissue repair by regeneration enhancer elements. Nature 2016;532:201.
  4. Sun X, Chuang J-C, Kanchwala M, et al., Suppression of the SWI/SNF Component <em>Arid1a</em> Promotes Mammalian Regeneration. Cell Stem Cell 2016;18:456-466.
  5. Chuong EB, Elde NC, and Feschotte C, Regulatory activities of transposable elements: from conflicts to benefits. Nature Reviews Genetics 2016;18:71.
  6. Michalopoulos GK, Liver regeneration. Journal of Cellular Physiology 2007;213:286-300.
  7. Taub R, Liver regeneration: from myth to mechanism. Nature Reviews Molecular Cell Biology 2004;5:836-847.
  8. Wang S, Zhang C, Hasson D, et al., Epigenetic Compensation Promotes Liver Regeneration. Developmental Cell 2019;50:43-56.e6.