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The crosstalk of DNA and lysine methyltransferases in ADPKD.

ADPKD 中 DNA 和赖氨酸甲基转移酶的串扰。

基本信息

批准号：
10680391
负责人：
Xiaogang Li
金额：
$ 48.43万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680391
关键词：
Address Affect Apoptosis Autosomal Dominant Polycystic Kidney Body Regions Cells ChIP-seq Cyst Cystic kidney DNA DNA Methylation DNA Methylation Regulation DNA Modification Methylases DNA Sequence Alteration Disease Progression Enzymes Epigenetic Process Epithelial Cell Proliferation Epithelial Cells FRAP1 gene Family Feedback Gene Expression Gene Proteins Genes Genetic Genetic Transcription Genome Growth Histone Deacetylase Histones Human Human Genome Hydralazine Hypermethylation Investigation Kidney Kidney Diseases Knock-out Knockout Mice Link Lysine Maintenance Malignant Neoplasms Mediating Methylation Methyltransferase Molecular Mus Mutation Patients Play Polycystic Kidney Diseases Process Regulation Repression Role SET Domain STAT3 gene Severity of illness Signal Pathway Signal Transduction System TP53 gene Testing Therapeutic Tissues Up-Regulation bisulfite sequencing cilium biogenesis conditional knockout demethylation epigenetic regulation genome-wide analysis histone methylation histone methyltransferase human disease in vivo inhibitor methylation pattern mouse model mutant new therapeutic target novel protein function recruit renal epithelium survivin translational potential whole genome

项目摘要

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in one of two genes, PKD1 or PKD2, whereas it cannot be fully understood in terms of the constrained genetic setting, especially, in families with the same genetic mutations but variable disease severity. Epigenetic regulation as a critical driver of cell fate and survival can occur even in genetically identical humans, which may be an alternative means of explaining PKD-associated alterations. Thus, the roles of epigenetic modulation of gene expression and protein functions in ADPKD should become the focus of scientific investigation. However, in addition to histone deacetylases (HDACs), the roles of DNA and histone methylation and the enzymes that mediate these processes in ADPKD remain largely unexplored. PKD1 is hypermethylated in gene-body regions and its expression is downregulated in ADPKD. By performing whole-genome bisulfite sequencing (WGBS) analysis, we have identified the genome-wide abnormal DNA methylation signatures in ADPKD kidneys compared to those in normal kidneys, suggesting that DNA methylation is one of the key mechanisms underlying cystogenesis. Within the five DNA methyltransferases, DNMT1 is the only enzyme that functions to maintain the DNA methylation patterns in human genome. DNMT1 was upregulated in Pkd1 mutant renal epithelial cells and tissues, implying its role in the maintenance of the abnormal DNA methylation signatures in ADPKD genome. We will investigate the roles and mechanisms of DNMT1 in regulating renal cyst progression in aim 1. Since we identified an interaction between DNMT1 and Smyd2, one of the SET- domain-containing histone (lysine) methyltransferases, it suggested that Smyd2 may be involved in DNMT1 mediated DNA methylation. We will investigate the crosstalk of DNMT1 and Smyd2 in the regulation of DNA methylation and further delineate Smyd2-mediated molecular mechanisms in the regulation of cystogenesis in aim 2, which may address if Smyd2 serves as a recruitment platform for DNMT1 on specific gene methylation, thus highlighting a previously unrecognized direct connection between two key epigenetic repression systems and providing a possible explanation of why the upregulation of DNMT1 in cancer and PKD only targets specific genes but not all genes in patients’ genome. Furthermore, we will test if de- methylation of hypermethylated DNA mediated by DNMT1 with Hydralazine and Smyd2 inhibitor delays cyst growth in vivo in aim 3. This is the first study that not only links DNMT1 and DNA methylation to ADPKD but also links the corresponding DNMT1 and Smyd2 signaling together in regulation of DNA methylation and gene expression. In addition, this study will produce information that will be therapeutically relevant with excelling potential for translation.

摘要常染色体显性遗传性多囊肾病(ADPKD)是由两种基因中的一种突变引起的， PKD1或PKD2，但在受限的遗传环境下不能完全理解它，特别是，在具有相同基因突变但疾病严重程度不同的家庭中。表观遗传调控是关键即使在基因相同的人类中，细胞命运和生存的驱动因素也可能发生，这可能是另一种选择解释与PKD相关的改变的方法。因此，表观遗传调控基因表达的作用 ADPKD的蛋白质功能应成为科学研究的重点。然而，除了组蛋白脱乙酰酶、DNA和组蛋白甲基化的作用及其介导酶 ADPKD的这些过程在很大程度上仍未被探索。PKD1在基因体区域高度甲基化，在ADPKD中其表达下调。通过执行全基因组亚硫酸氢盐测序(WGBS) 分析，我们已经确定了ADPKD肾脏全基因组范围的异常DNA甲基化特征与正常肾脏相比，提示DNA甲基化是其关键机制之一潜在的囊变。在五种DNA甲基转移酶中，DNMT1是唯一起作用的酶以维持人类基因组中的DNA甲基化模式。DNMT1在PKD1突变肾中表达上调上皮细胞和组织，暗示其在维持异常DNA甲基化特征中的作用在ADPKD基因组中。我们将研究DNMT1在调节肾囊肿中的作用和机制。目标1的进展。由于我们确定了DNMT1和Smyd2之间的相互作用，其中一个集合- 含有结构域的组蛋白(赖氨酸)甲基转移酶，提示Smyd2可能参与了DNMT1 介导的DNA甲基化。我们将研究DNMT1和Smyd2在DNA调控中的串扰甲基化及其进一步阐明Smyd2介导的囊变调控的分子机制在目标2中，它可能解决Smyd2是否作为特定基因上DNMT1的招募平台甲基化，从而突出了两个关键的表观遗传学之间以前未被认识到的直接联系抑制系统，并提供了一个可能的解释为什么DNMT1在癌症和 PKD只针对特定的基因，而不是患者基因组中的所有基因。此外，我们将测试是否去- 联苯肼和Smyd2抑制剂介导的DNMT1高甲基化DNA甲基化延缓囊肿这是第一个不仅将DNMT1和DNA甲基化与ADPKD联系起来的研究，而且也将相应的DNMT1和Smyd2信号连接在一起，调节DNA甲基化和基因表达。此外，这项研究将提供与治疗相关的信息翻译潜力超群。