25 October 2021
Identifying the gene regulators of liver regeneration
Published online 15 July 2021
In the mouse liver, epigenetics keeps some genes in a ‘ready-set’ state.
The liver keeps some genes in a ready-set state, awaiting the go signal that instructs tissue regeneration. Specific epigenetic modifications — changes that regulate gene expression without altering the DNA sequence — could explain how the liver rebuilds itself quickly after chemical damage or surgical procedures.
Epigenetic modifications encourage or silence gene expression by opening or closing the chromatin that densely packs DNA inside the nucleus. Chromatin is bivalent when activating and repressing epigenetic marks coexist. Bivalency was discovered in embryonic stem cells, and has since primarily been studied in the context of development and cancer, where quick gene activation may be crucial. More recently it has been detected in certain cancer and healthy adult tissues.
Even though thousands of genes are known to turn on or off during liver regeneration, the role of epigenetics in this process has not been thoroughly analysed.
Researchers at New York University Abu Dhabi (NYUAD) in the United Arab Emirates analysed the genome of the mature mouse liver, and found genes involved in cell cycle control and proliferation residing in bivalent chromatin. The genes are kept silent by a repressive epigenetic mark, called H3K27me3, in what is otherwise active, open chromatin. When the liver needs to regenerate, this mark is depleted from the genes, enabling gene expression and driving proliferation.
“Genes are ‘ready and set’ in the healthy liver, but kept from ‘go’ by the repressive epigenetic mark, H3K27me3. When the liver is stimulated to regenerate, H3K27me3 is removed from these genes allowing them to go, promoting regeneration,” says biologist, Kirsten Sadler Edepli, who led this study.
“While the study does not clarify how the H3K27me3 mark is lost during regeneration, it provides a foundation for understanding chromatin changes during regeneration and identifying targets to try to enhance the process,” says Kenneth S. Zaret of the Institute for Regenerative Medicine, University of Pennsylvania, US, who was not involved in this study.
Edepli says their finding opens many questions. For instance, does the epigenome reset after regeneration, or is there an epigenetic memory of regeneration? Is the loss of regenerative capacity in aged animals due to fact that pro-regenerative genes are now in a closed state? And finally, what are the factors that write these marks?
Zhang, Chi et al. "Chromatin states shaped by an epigenetic code confer regenerative potential to the mouse liver." Nat. Commun. 12.1, 1-16 (2021).