Epigenetic Regulation of Development and Liver Regeneration by UHRF1

UHRF1 对发育和肝脏再生的表观遗传调控

基本信息

批准号：
9293301
负责人：
Kirsten C Sadler Edepli
金额：
$ 47.87万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-09 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9293301
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 Modification Methylases DNA Modification Process Data Data Set Defect Development Embryo Engineering Enzymes Epigenetic Process Event Excision Gene Expression Gene Expression Profiling Genes Genetic Transcription 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 PHD Finger Partial Hepatectomy Patients Pattern Phenotype Phosphorylation Play Post-Translational Protein Processing Process Proliferating Proteins Recovery Recruitment Activity Regenerative response Regulation Regulator Genes Repression Ring Finger Domain Role Serine Stimulus Testing Toxin Transcriptional Activation Transferase Trauma Ubiquitin Virus Diseases Work Writing Zebrafish base chromatin remodeling cofactor comparative epigenetic regulation epigenome epigenomics experimental study gene induction genome-wide improved improved outcome insight liver cell proliferation liver development liver transplantation methylome mutant public health relevance regenerative response transcriptome

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对发育和肝脏再生的表观遗传调节肝脏再生能够使病毒感染、毒素、创伤、缺血和切除造成的损伤恢复。在没有损伤的情况下，分化的肝细胞处于静止状态，但是当肝脏质量受到损害时，例如当肝脏的一部分被切除时，肝细胞就会“苏醒”并重新进入细胞周期。这伴随着数百个驱动增殖的基因的转录激活，一旦肝脏大小恢复到原来的水平，这些相同的基因就会受到抑制。胚胎肝脏发育过程中也发生类似的过程，分化的肝细胞迅速增殖，产生大小成比例的肝脏。尽管肝脏的发育和再生是针对非常不同的刺激而发生的，但它们具有重要的相似之处。也就是说，这两个过程的特点是诱导数百个基因并同时抑制其他基因，并且需要包含 PHD 和 RING Finger 结构域 - 1 (Uhrf1) 的泛素。 Uhrf1 既“读取”修饰后的组蛋白代码，又通过招募组蛋白修饰酶和 DNA 甲基转移酶 (DNMT1)“写入”该代码。这些复杂的功能被认为介导控制基因表达的动态和多层抑制性表观遗传标记，并且新出现的证据表明表观遗传修饰在细胞分裂过程中调节染色质动力学中发挥重要作用。我们假设 Uhrf1 在肝脏再生和发育过程中通过甲基化组介导的直接和间接作用来调节细胞周期进程。我们将利用基因表达的生化、遗传和生物信息分析，结合甲基化 DNA 和 Uhrf1 的全基因组占据，来确定小鼠肝脏再生和斑马鱼肝脏生长的表观遗传控制机制。在目标 1 中，我们将使用经过肝细胞特异性敲除 Uhrf1 的小鼠进行肝脏再生方面的一些首次表观遗传学研究。目标 2 将确定 Uhrf1 在斑马鱼肝脏生长过程中如何调节相同的表观遗传修饰。然后，我们将率先使用比较表观基因组学来识别 Uhrf1 介导的表观遗传修饰的保守和不同模式。目标 3 的工作基于我们的发现，即 Uhrf1 上保守丝氨酸的磷酸化对其功能至关重要。我们将阐明磷酸化如何调节 Uhrf1 基因组占据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耗尽的肝细胞在再生或发育过程中甲基化组和转录组的变化，我们将在表观遗传调节因子、基因表达变化和细胞增殖之间产生因果关系。这与两个重要领域直接相关：我们将通过阐明操纵再生的机制来推进肝病的潜能疗法，并将深入了解胚胎器官特异性发育过程中表观基因组的模式。