Epigenetic events can promote liver regeneration in mice

Last Updated: 2019-07-03

By Will Boggs MD

NEW YORK (Reuters Health) - Epigenetic events can contribute to liver regeneration, according to studies in mice.

"So much work in the epigenetics field is gene-centric; however, our work along with many other studies coming out now from other groups, is refocusing on the other regions of the genome," said Dr. Kirsten Sadler Edepli from Icahn School of Medicine at Mount Sinai, in New York City, and New York University Abu Dhabi, in United Arab Emirates.

"What we used to think of as 'junk' we now know is full of regulator regions and is littered with transposons," she told Reuters Health by email.

Major functions of the epigenome include regulation of gene expression and suppression of transposons that can restructure the genome, causing genomic instability and cell death. How these functions are balanced during liver regeneration remains unclear.

Dr. Edepli's team found that the epigenetic regulator UHRF1, which is essential for DNA methylation (the mainstay of defense against transposon activation), was dynamically expressed during liver regeneration in mice.

Deletion of UHRF1 in hepatocytes of mice caused genome-wide DNA hypomethylation, as expected, but this had no measurable effect on gene or transposon expression or on liver homeostasis, the researchers report Developmental Cell, online June 20.

Partial hepatectomy of UHRF1-knockout livers was followed by early and sustained activation of regenerative genes and enhanced liver regeneration. This appeared to result from redistribution of the epigenetic mark H3K27me from the promoters of genes required for liver regeneration to hypomethylated transposons, thereby repressing them.

"The initial hypothesis was that when Uhrf1 was removed from hepatocytes, the cells would either die or fail to divide due to activation of a cell-cycle block to prevent cells with epigenetic damage from propagating - reflecting our findings during liver growth in zebrafish embryos," Dr. Edepli said. "To our surprise, we found the exact opposite - that Uhrf1-deficient hepatocytes responded better to mitogenic stimuli - no cell-cycle block and no cell death! I found it hard to believe, but that paradox is what made the work so exciting."

"We are very motivated by figuring out how we can harness the epigenome to help the liver regenerate better in the case of hepatic damage or liver failure," she said.

"Ideally, we would be able to harness the ability to promote regeneration in settings of liver failure or in the setting of small for sized organ transplantation," Dr. Edepli said. "However, this needs to be balanced with the potential for activating transposons, which can lead to widespread genomic instability and the potential for promoting cancer when regenerative capacity is enhanced."

"Until we understand how cells and whole organisms compensate for epigenetic changes, I think that cautious optimism is the best approach," she concluded.

Dr. Bor-Sen Chen from National Tsing Hua University, in Hsinchu, Taiwan, who recently differentiated mechanisms between normal, developing, and regenerating livers as a step toward regenerative liver drug design, told Reuters Health by email, "If we know the procedure of epigenetic compensation resulting in the enhanced liver regeneration, the corresponding epigenetic biomarkers are worth clinical trial for developing new therapeutic treatments of liver disease and liver failure."

"The molecular mechanisms triggered by cascade signaling pathways during hepatogenesis are complicated," said Dr. Chen, who was not involved in the new work. "By combining wet-lab experiments with systematic approaches by leveraging heterogeneous data, we not only could understand the liver regeneration comprehensively but also accelerate the drug discovery."

SOURCE: https://bit.ly/2IPKYuu

Dev Cell 2019.