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.

项目摘要年轻哺乳动物中肝的显着再生潜力是由于静止的能力肝细胞灵活应对有丝分裂信号。这取决于协调良好的基因调节我们建议的程序嵌入了肝性表观基因组中。表观基因组在调节基因表达并保护细胞免受转座元件（TE）的威胁，如果释放会导致DNA损伤和基因组不稳定性。表观遗传标记的复杂组合将基因组组织到区域（即染色质状态），该区域决定哪些区域保持开放以及哪些区域保持关闭。封闭的染色质状态包含沉默的基因和大多数TE。开放染色质状态包含积极转录的基因以及以中毒构型为信号的基因这改变了它们的表达以改变细胞功能或身份。我们发现促进的基因肝脏再生在静止生命中有毒，具有反射性（H3K27ME3）和激活（H3K4ME3）标记。由于在再生期间这些基因上丢失了H3K27me3，因此我们包括这是表观遗传守则承认年轻生活的再生潜力。我们发现了惊喜的灵活性在该代码中，通过研究表观遗传调节剂UHRF1，这对于维持DNA至关重要 DNA复制过程中的甲基化。我们发现肝细胞中的UHRF1损失（UHRF1HEPKO）导致全球 DNA低甲基化，但没有激活TE。我们将其归因于表观遗传补偿 H3K27me3，它富集于降低甲基化TE并从UHRF1HEPKO中的启动子耗尽小鼠，促增生基因和加速肝脏再生的伴随过早激活在这些老鼠中。我们的中心假设是年轻的表观遗传代码允许转录因子在限制访问TE的同时，访问亲获得基因，并且该代码已重写在衰老期间，导致TE激活和再生下降。我们进一步假设UHRF1和 H3K27me3是此代码的关键元素。为了测试这一点，我们将确定年轻的UHRF1Hepko肝中的表观遗传补偿，并将检查H3K27me3在Pro-中的作用野生型生命中的再生基因调节（AIM 1）。通过整合表观基因组和转录组学与年轻生活中的染色质状态相比，老年老鼠和人类生活的谱分析，我们将建立衰老如何重塑肝表观基因组以抑制促进基因并激活TES（AIM 2）。在AIM 3中，我们探讨了耗尽的H3K27me3是否可以使肝脏恢复活力。在一起的结果工作将揭示表观基因组的双重作用 - 基因调节和转座子的抑制威胁 - 整合在调节年轻小鼠的肝脏再生中，并将为操纵表观基因组，以增强古老的疾病和患有肝脏的人的再生潜力失败。

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.