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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.

项目摘要幼年哺乳动物肝脏的显著再生潜力是由于其静止的能力。肝细胞能够灵活地对有丝分裂信号做出反应。这依赖于一种协调良好的基因调控程序，我们建议将其嵌入到肝脏表观基因组中。表观基因组在在调节基因表达和保护细胞免受转座元件(TES)威胁方面，如果释放会导致DNA损伤和基因组不稳定。表观遗传标记的复杂组合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，哪些区域保持开放闭上眼睛。封闭的染色质状态包括沉默的基因和大多数TES。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构型的基因通过改变它们的表达来改变细胞功能或身份。我们发现促进基因肝再生处于静止状态，有抑制性(H3K27me3)和激活性(H3K4me3) 马克。由于H3K27me3在再生过程中在这些基因上丢失，我们得出结论，这是赋予年轻肝脏再生潜力的表观遗传密码。我们发现了一个令人惊讶的灵活性通过研究表观遗传调节因子uhrf1，它对维持dna是必不可少的。 DNA复制过程中的甲基化。我们发现Uhrf1在肝细胞中的丢失(Uhrf1HepKO)导致全局 DNA低甲基化，但不激活TES。我们将此归因于表观遗传补偿 H3K27me3，在Uhrf1HepKO中变得富含低甲基化的TES，而从启动子中耗尽小鼠，伴随促再生基因的过早激活和肝再生的加速在这些老鼠身上。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TES，并重写此代码在老化过程中，导致TE激活和再生能力下降。我们进一步假设uhrf1和 H3K27me3是该代码的关键元素。为了测试这一点，我们将确定在年轻的Uhrf1HepKO肝脏中的表观遗传代偿，并将研究H3K27me3在促进- 野生型肝脏中再生基因的调控(目标1)。通过整合表观基因组和转录组比较老化的小鼠和人的肝脏与年轻肝脏中的染色质状态，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和激活TES(目标2)。在目标3中，我们探索耗尽H3K27me3是否可以恢复肝脏活力。总而言之，这一结果工作将揭示表观基因组基因的双重作用是如何调节和抑制转座子的威胁-整合在调节幼鼠肝脏再生的过程中，并将为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了。

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

Zebrafish: an important tool for liver disease research.