Epigenetic regulation of development and liver regeneration by UHRF1

UHRF1 对发育和肝再生的表观遗传调控

基本信息

批准号：
8695893
负责人：
Kirsten C Sadler Edepli
金额：
$ 56.93万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2009-02-10 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8695893
关键词：
Affect Automobile Driving Binding Binding Proteins Biochemical Biochemical Genetics Bioinformatics Biological Cell Cycle Cell Cycle Progression Cell Differentiation process Cell Proliferation Cell division Cells Chromatin Chromatin Structure Code Complex DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA Modification Process Data Data Set Defect Development Embryo Engineering Enzymes Epigenetic Process Event Excision Fingers Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genomics Global Change Goals Hepatic Hepatic Mass Hepatocyte Histone Code Histones Human Injury Ischemia Knock-out Liver Liver Failure Liver Regeneration Liver diseases Mediating Modeling Modification Mus Natural regeneration Organ Outcome Partial Hepatectomy Patients Pattern Phenotype Phosphorylation Play Process Proliferating Proteins Reading Recovery Recruitment Activity Regulation Regulator Genes Repression Role Serine Stimulus Testing Toxin Transcriptional Activation Transferase Trauma Ubiquitin Virus Diseases Work Writing Zebrafish base chromatin remodeling cofactor comparative epigenome epigenomics gene induction genome-wide improved insight liver cell proliferation liver transplantation methylome mutant public health relevance regenerative research study response

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：UHRF1肝脏再生对发育和肝脏再生的表观遗传调节，可从病毒感染，毒素，创伤，缺血和切除引起的损伤中恢复。在没有损伤的情况下，分化的肝细胞是静止的，但是当肝脏被损害时，例如，当肝脏的一部分被去除时，肝细胞“醒来”并重新进入细胞周期。这伴随着数百种驱动增殖的基因的转录激活，一旦恢复了原始肝脏大小，这些相同的基因就会被抑制。在胚胎的肝发育过程中发生了类似的过程，在胚胎中，分化的肝细胞迅速增殖以产生比例大小的肝脏。尽管肝脏发育和再生是响应非常不同的刺激而发生的，但它们具有重要的相似性。也就是说，这两个过程的特征是诱导数百个基因和同时抑制他人，并且需要泛素蛋白，例如包含PhD和Ringfinger域1（UHRF1）。 UHRF1都通过募集组蛋白修饰酶和DNA甲基转移酶（DNMT1）来“读取”修饰的组蛋白代码和“写入”该代码。这些复杂的功能被认为可以介导控制基因表达的动态和多层抑制性表观遗传标记，并且出现的证据表明表观遗传修饰在调节细胞分裂过程中调节染色质动力学方面的重要作用。我们假设UHRF1通过在肝脏再生和发育过程中通过甲基介导的直接和间接效应调节细胞周期进程。我们将对基因表达的生化，遗传和生物信息学分析以及甲基化DNA和UHRF1的基因组广泛占用率，以确定小鼠肝脏再生的表观遗传控制以及斑马鱼中肝脏的产卵的基础机制。在AIM 1中，我们将使用我们用肝细胞特异性敲除UHRF1进行工程的小鼠进行肝脏再生的一些表观遗传学研究。 AIM 2将决定UHRF1如何调节斑马鱼肝脏生长期间相同的表观遗传修饰。然后，我们将开拓比较表观基因组学来识别由UHRF1介导的表观遗传修饰的保守和不同模式。 AIM 3中的工作是基于我们发现的，即UHRF1上保守的丝氨酸的磷酸化对于其功能至关重要。我们将阐明磷酸化如何调节UHRF1基因组占用率及其与结合伴侣的相互作用。通过精确定义细胞周期缺陷，UHRF1中甲基甲基和转录组的变化耗尽了经历或发育的肝细胞，我们将在基因表达变化和细胞增殖之间产生病因关系。这与两个重要领域具有直接相关性：我们将通过阐明一种机制来促进肝病的电位疗法，通过该疗法我们可以操纵再生，并将深入了解表观组在器官特定胚胎中如何在特定的胚胎发育过程中进行图案。