Epigenetic regulation of development and liver regeneration by UHRF1 Liver regeneration enables recovery from injury due to viral infection, toxins, trauma, ischemia and resection. In the absence of injury, differentiated hepatocytes are quiescent, but when liver mass is compromised such as occurs when a portion of the liver is removed, hepatocytes "awaken" and re-enter the cell cycle. This is accompanied by the transcriptional activation of hundreds of genes that drive proliferation and these same genes are repressed once the original liver size is recovered. A similar process occurs during liver development in embryos, where differentiated hepatocytes rapidly proliferate to generate a liver of proportional size. Although liver development and regeneration occur in response to very different stimuli, they share important similarities. Namely, both processes are characterized by induction of hundreds of genes and simultaneous repression of others, and which require Ubiquitin like containing PHD and RING Finger domains- 1 (Uhrf1). Uhrf1 both "reads" the modified histone code and "writes" this code by recruiting histone modifying enzymes and DNA methyl transferase (DNMT1). These complex functions are thought to mediate dynamic and multi-layered repressive epigenetic marks that control gene expression and, emerging evidence points to an important role for epigenetic modifications in regulating chromatin dynamics during cell division. We hypothesize that Uhrf1 regulates cell cycle progression via both direct and indirect effects mediated through the methylome during liver regeneration and development. We will use biochemical, genetic and bioinformatic analysis of gene expression combined with genome wide occupancy of methylated DNA and Uhrf1 to identify the mechanism underlying epigenetic control of liver regeneration in mice and hepatic outgrowth in zebra fish.
In Aim 1, we will undertake some of the first epigenetic studies in liver regeneration using mice we engineered with hepatocyte-specific knock out of Uhrf1.
Aim 2 will determine how Uhrf1 regulates the same epigenetic modifications during hepatic outgrowth in zebra fish. We will then pioneer the use of comparative epigenomics to identify conserved and divergent patterns of epigenetic modifications mediated by Uhrf1. Work in Aim 3 is based on our discovery that phosphorylation of a conserved serine on Uhrf1 is essential for its function. We will elucidate how phosphorylation regulates Uhrf1 genomic occupancy and its interaction with binding partners. By precisely defining the cell cycle defects, changes in the methylome and transcriptome in Uhrf1 depleted hepatocytes undergoing regeneration or development, we will generate causative relationships between an epigenetic regulator, gene expression changes and cell proliferation. This has direct relevance to two important fields: we will advance potentia therapies for liver disease by elucidating a mechanism by which we may manipulate regeneration and will provide insight into how the epigenome is patterned during organ specific development in embryos.
Epigenetic regulation of development and liver regeneration by UHRF1 Epigenetic modification of DNA and the proteins that organize DNA is a fundamental process controlling gene expression. We propose to uncover the mechanism by which the UHRF1 protein controls epigenetic events in liver development and liver regeneration. Our goal is that our discoveries will provide a platform to develop theraies that improve liver regeneration to treat patients with liver disease and improve the outcome of liver transplant.
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