Regulation of Liver Regeneration by UHRF1

UHRF1 对肝脏再生的调节

基本信息

批准号：
10659607
负责人：
Kirsten C Sadler Edepli
金额：
$ 24.2万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659607
关键词：
Acceleration Age Aging Animals Cell physiology Chromatin Code Compensation Complex Cytoprotection DNA DNA Damage DNA Methylation DNA Transposable Elements DNA biosynthesis Data Data Set E2F transcription factors EZH2 gene Elderly Elements Epigenetic Process Foundations Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Genome Genomic Instability Genomics Goals Health Hepatic Hepatocyte Human Inflammation Knock-out Link Liver Liver Failure Liver Regeneration Longevity Machine Learning Mammals Modification Molecular Multiomic Data Mus Natural regeneration Outcome Partial Hepatectomy Pattern Phenotype Process Proliferating Regenerative capacity Regulation Regulator Genes Rejuvenation Repression Role Signal Transduction Testing Therapeutic Intervention Work Writing access restrictions aged epigenome epigenomic profiling epigenomics flexibility gene discovery genetic approach healthspan juvenile animal liver function novel strategies older patient pharmacologic premature prevent programs promoter regeneration potential regenerative response therapy development transcription factor transcriptomic profiling transcriptomics

项目摘要

Project Summary The remarkable regenerative potential of the liver in young mammals is due to the ability of quiescent hepatocytes to nimbly respond to mitogenic signals. This relies on a well-coordinated gene regulatory program, which we propose is embedded in the hepatic epigenome. The epigenome serves dual roles in regulating gene expression and in protecting cells from the threat of transposable elements (TEs), which if unleashed can cause DNA damage and genomic instability. A complex combination of epigenetic marks organizes the genome into regions (i.e. chromatin states) which dictate which regions stay open and which stay closed. Closed chromatin states encompass silenced genes and most TEs. Open chromatin states contain actively transcribed genes as well as genes held in a poised configuration in anticipation of signals that alter their expression to change cellular function or identity. We discovered that genes that promote liver regeneration are poised in quiescent livers, with repressive (H3K27me3) and activating (H3K4me3) marks. Since H3K27me3 was lost on these genes during regeneration, we conclude this is a key element of the epigenetic code that confers regenerative potential to young livers. We uncovered a surprising flexibility in this code through studying the epigenetic regulator, UHRF1, which is essential for maintaining DNA methylation during DNA replication. We found that Uhrf1 loss in hepatocytes (Uhrf1HepKO) resulted in global DNA hypomethylation, but did not activate TEs. We attributed this to epigenetic compensation by H3K27me3, which became enriched on hypomethylated TEs and depleted from promoters in Uhrf1HepKO mice, with a concomitant premature activation of pro-regenerative genes and accelerated liver regeneration in these mice. Our central hypothesis is that the youthful epigenetic code permits transcription factor access to pro-regenerative genes while restricting access to TEs, and that this code is rewritten during aging, resulting in TE activation and regenerative decline. We further hypothesize that UHRF1 and H3K27me3 are key elements of this code. To test this, we will identify the molecular mechanisms of epigenetic compensation in young Uhrf1HepKO livers and will examine the role of H3K27me3 in pro- regenerative genes regulation in wild type livers (Aim 1). By Integrating epigenomic and transcriptomic profiling of aged mouse and human livers compared to chromatin states in young livers, we will establish how aging repatterns the hepatic epigenome to repress pro-regenerative genes and activate TEs (Aim 2). In Aim 3, we explore whether depleting H3K27me3 can rejuvenate the liver. Together, the outcomes of this work will uncover how the dual roles of the epigenome – gene regulation and suppression of transposon threat – are integrated in regulating liver regeneration in young mice and will provide a foundation to manipulate the epigenome to augment regenerative potential in the elderly and those suffering from liver failure.

项目概要年轻哺乳动物的肝脏具有显着的再生潜力，这是由于其具有静止状态的能力肝细胞对有丝分裂信号的灵活反应依赖于良好协调的基因调控。我们建议将其嵌入肝脏表观基因组中，表观基因组在其中发挥双重作用。调节基因表达并保护细胞免受转座元件（TE）的威胁，如果释放的表观遗传标记会导致 DNA 损伤和基因组不稳定。将基因组组织成区域（即染色质状态），这些区域决定哪些区域保持开放以及哪些区域保持开放关闭染色质状态包含沉默基因和大多数开放染色质状态。包含活跃转录的基因以及在预期信号时保持稳定配置的基因改变它们的表达以改变细胞功能或身份我们发现促进基因。肝脏再生在静止的肝脏中做好准备，具有抑制性（H3K27me3）和激活性（H3K4me3）由于 H3K27me3 在再生过程中在这些基因上丢失，我们得出结论这是一个关键元素。我们发现赋予年轻肝脏再生潜力的表观遗传密码具有令人惊讶的灵活性。通过研究表观遗传调节因子 UHRF1，该密码对于维持 DNA 至关重要我们发现肝细胞中的 Uhrf1 丢失（Uhrf1HepKO）导致了整体的 DNA 复制过程中的甲基化。 DNA 低甲基化，但没有激活 TE，我们将此归因于表观遗传补偿。 H3K27me3，在 Uhrf1HepKO 中低甲基化 TE 富集并耗尽启动子小鼠，伴随着促再生基因的过早激活并加速肝脏再生我们的中心假设是年轻的表观遗传密码允许转录因子。访问促再生基因，同时限制访问 TE，并且该代码被重写在衰老过程中，导致 TE 激活和再生能力下降，我们进一步研究了 UHRF1 和 H3K27me3 是该代码的关键元素。为了测试这一点，我们将确定其分子机制。年轻的 Uhrf1HepKO 肝脏中的表观遗传补偿，并将检查 H3K27me3 在亲- 野生型肝脏中的再生基因调控（目标 1）。与年轻肝脏的染色质状态相比，对老年小鼠和人类肝脏进行分析，我们将建立衰老如何重塑肝脏表观基因组以抑制促再生基因并激活 TE（目标 2）。在目标 3 中，我们探讨消耗 H3K27me3 是否可以使肝脏恢复活力。这项工作将揭示表观基因组的双重作用——基因调控和转座子抑制威胁——被整合到调节年轻小鼠的肝脏再生中，并将为以下方面提供基础：操纵表观基因组以增强老年人和肝病患者的再生潜力失败。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

UHRF1 depletion causes a G2/M arrest, activation of DNA damage response and apoptosis.

DOI：
10.1042/bj20100840
发表时间：
2011-04-01
期刊：
The Biochemical journal
影响因子：
0
作者：
Tien AL;Senbanerjee S;Kulkarni A;Mudbhary R;Goudreau B;Ganesan S;Sadler KC;Ukomadu C
通讯作者：
Ukomadu C

High resolution annotation of zebrafish transcriptome using long-read sequencing.