Histone Deacetylases and Kidney Development

组蛋白脱乙酰酶和肾脏发育

• 批准号: 7938586
• 负责人: Samir S El-Dahr
• 金额: $ 33.43万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938586
• 关键词: 4 year old; Accounting; Apoptosis; Binding; Biochemical; Cardiovascular system; Cell Culture System; Cell Cycle Arrest; Cell Death; Cell Lineage; Cell Nucleus; Cell Proliferation; Cells; Child; Chromatin Structure; Chronic Kidney Failure; Clinical; Code; Congenital Abnormality; DNA; DNA Microarray Chip; DNA Sequence; DNA-Binding Proteins; Data; Defect; Development; Developmental Process; Differentiation and Growth; Embryo; Embryonic Development; Environmental Exposure; Enzymes; Epigenetic Process; Equilibrium; Exhibits; Figs - dietary; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Code; Genetic Programming; Growth; HDAC1 gene; HDAC2 gene; Histone Acetylation; Histone Code; Histone Deacetylase; Histones; Immune System Diseases; In Situ; Infant; Kidney; Kidney Failure; Maintenance; Malignant Neoplasms; Mediating; Mesenchyme; Metanephric Diverticulum; Microarray Analysis; Modification; Mus; Mutation; Nephrons; Nucleosomes; Organogenesis; Pathway interactions; Pattern; Pharmaceutical Preparations; Physiological; Play; Prevention; Proliferating; Proteins; Reading; Regulation; Regulator Genes; Role; Stromal Cells; Time; Toxin; Transcription Repressor/Corepressor; Urinary tract; Vesicle; Virus Diseases; Work; combinatorial; design; epithelial Na+ channel; fetal; histone acetyltransferase; histone methyltransferase; in vivo; insight; malformation; nephrogenesis; premature; prevent; programs; promoter; protein complex; research study; role model; spatiotemporal; transcription factor

DESCRIPTION (provided by applicant): Mounting evidence indicates that alterations in chromatin structure and function induce specific and significant changes in gene expression. Histone deacetylases (HDACs) are an evolutionarily conserved class of enzymes which remove acetyl groups from histones and compacts the nucleosome and thus prevents access of DNA-binding proteins to DNA. Moreover, HDACs, along with histone methyltransferases and other histone modifiers, create an "epigenetic code" that is read by transcriptional repressors or activators. Histone acetylation plays important roles in cancer, immune disorders and embryonic development. In the mouse, targeted inactivation of HDAC1 and HDAC2 genes causes embryonic lethality precluding the analysis of kidney development. The overall aim of this proposal is to elucidate the nephric lineage-specific functions of HDAC1/2. Our preliminary data indicate that HDAC 1 and HDAC2 are expressed in both compartments of the developing kidney, the metanephric mesenchyme (MM) and ureteric bud (UB), in a developmentally regulated manner. Pharmacological inhibition of metanephric HDAC activity induces lineage-specific and time-dependent changes in gene expression, compromises metanephric proliferation, and provokes premature differentiation. We therefore propose that HDAC 1 and HDAC 2 perform essential roles in the epigenetic control of kidney development: 1) in the MM, HDAC1/2 are required for maintained expression of the Eya1 and Foxd1 genes as well as survival and renewal of MM cells; 2) in the UB, HDAC1/2 maintain the pool of tip Ret+/Wnt11+ cells and repress the terminal differentiation program. We will use a variety of genetic and biochemical approaches, together with organotypic and cell culture systems, to conduct the following specific aims: 1) Elucidate the developmental processes and lineage-specific morphogenetic pathways that are dependent on HDACs during metanephric development; 2) Determine the contribution of HDAC1/2 to the regulation of the Gdnf-Ret-Wnt11 pathway; and 2) Identify HDAC-sensitive gene regulatory networks in the MM and UB lineages. The results will provide new insights into the epigenetic control of organogenesis and have important clinical implications as abnormal renal development is the leading cause of chronic renal failure in infants and children. PUBLIC HEALTH RELEVANCE: Congenital malformations of the kidney and urinary tract account for up to 40% of chronic kidney failure in children less than 4 years of age. In addition to mutations in the DNA sequence, abnormal kidney development may result from alterations in the "epigenetic code" which lies in the proteins around which the DNA is wrapped in the nucleus of the cell. Stable alterations in the epigenetic code resulting from transient environmental exposures (e.g., toxins, drugs, viral infections) can disrupt fetal gene expression without altering the DNA sequence. Thus, understanding the epigenetic regulation of kidney development may open new avenues to the treatment or prevention of kidney and urinary tract malformations and kidney failure.

描述（由申请人提供）：越来越多的证据表明，染色质结构和功能的改变诱导基因表达的特异性和显著变化。组蛋白脱乙酰酶（HDAC）是一类进化上保守的酶，其从组蛋白去除乙酰基并使核小体致密化，从而阻止DNA结合蛋白接近DNA。此外，HDAC与组蛋白甲基转移酶和其他组蛋白修饰剂一起沿着产生由转录阻遏物或激活物读取的“表观遗传密码”。组蛋白乙酰化在癌症、免疫紊乱和胚胎发育中起重要作用。在小鼠中，HDAC 1和HDAC 2基因的靶向失活导致胚胎致死，从而妨碍了肾脏发育的分析。该建议的总体目标是阐明HDAC 1/2的肾脏谱系特异性功能。我们的初步数据表明，HDAC 1和HDAC 2的表达在两个隔室的发展中的肾脏，后肾间充质（MM）和输尿管芽（UB），在一个发育调节的方式。后肾HDAC活性的药理学抑制诱导基因表达的谱系特异性和时间依赖性变化，损害后肾增殖，并引起过早分化。因此，我们认为HDAC 1和HDAC 2在肾脏发育的表观遗传控制中发挥重要作用：1）在MM中，HDAC 1/2是维持Eya 1和Foxd 1基因表达以及MM细胞存活和更新所必需的; 2）在UB中，HDAC 1/2维持尖端Ret+/Wnt 11+细胞池并抑制终末分化程序。我们将使用多种遗传学和生物化学方法，结合器官型和细胞培养系统，进行以下具体目标：1）阐明后肾发育过程中依赖HDAC的发育过程和谱系特异性形态发生途径; 2）确定HDAC 1/2对Gdnf-Ret-Wnt 11途径的调节作用;和2）鉴定MM和UB谱系中HDAC敏感的基因调控网络。这些结果将为器官发生的表观遗传控制提供新的见解，并具有重要的临床意义，因为肾脏发育异常是婴儿和儿童慢性肾功能衰竭的主要原因。公共卫生相关性：在4岁以下的儿童中，先天性肾脏和泌尿道畸形占慢性肾衰竭的40%。除了DNA序列的突变，肾脏发育异常可能是由于“表观遗传密码”的改变，表观遗传密码位于细胞核中DNA包裹的蛋白质中。由短暂环境暴露引起的表观遗传密码的稳定改变（例如，毒素、药物、病毒感染）可以破坏胎儿基因表达而不改变DNA序列。因此，了解肾脏发育的表观遗传调控可能为治疗或预防肾脏和尿路畸形以及肾衰竭开辟新的途径。