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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：
10092241
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/10092241
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 DNA-lysine adduct 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 Histone-Lysine N-Methyltransferase Human Human Genome Hydralazine Investigation Kidney Kidney Diseases Knock-out Knockout Mice Link Maintenance Malignant Neoplasms Mediating Methylation Methyltransferase Molecular Mus Mutation Patients Play Process Regulation Repression Role SET Domain STAT3 gene Severity of illness Signal Pathway Signal Transduction System TP53 gene Testing Therapeutic Tissues Translations Up-Regulation bisulfite sequencing cilium biogenesis conditional knockout epigenetic regulation genome-wide histone methylation histone methyltransferase human disease in vivo inhibitor/antagonist methylation pattern mouse model mutant new therapeutic target novel protein function recruit renal epithelium survivin 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