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Principal Investigator: Xiaogang Li
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2024
Award: $464,959
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <1(2H)-Phthalazinone, hydrazone><ADPKD><Address><Adult Polycystic Kidney Disease><Affect><Antioncogene Protein p53><Apoptosis><Apoptosis Inhibitor 4><Apoptosis Inhibitor Survivin><Apoptosis Pathway><Apresoline><Apressin><Autosomal Dominant Polycystic Kidney><Autosomal Dominant Polycystic Kidney Disease><BS-seq><Baculoviral IAP Repeat-Containing Protein 5><Bisulfite-based sequencing><Body Regions><Body Tissues><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Tumor Antigen P53><ChIP Sequencing><ChIP-seq><ChIPseq><Cyst><Cystic kidney><DNA><DNA Alteration><DNA Methylation><DNA Methylation Regulation><DNA Methyltransferase><DNA Modification Methylases><DNA Modification Methyltransferases><DNA Sequence Alteration><DNA mutation><DNA-Methyltransferases><Deoxyribonucleic Acid><Disease Progression><Dnmt><Dominant Polycystic Kidney Disease><EC 2.1.1><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cell Proliferation><Epithelial Cells><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Family><Feedback><Gene Expression><Gene Proteins><Gene Transcription><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genetic mutation><Genome><Growth><HDAC><HDAC Proteins><Histone Deacetylase><Histones><Human><Human Genome><Hydralazine><Hydrazinophthalazine><Hypermethylation><Intracellular Communication and Signaling><Investigation><KO mice><Kidney><Kidney Cyst><Kidney Diseases><Kidney Urinary System><Knock-out><Knock-out Mice><Knockout><Knockout Mice><L-Lysine><Link><Lysine><Maintenance><Malignant Neoplasms><Malignant Tumor><Mechanistic Target of Rapamycin><Mediating><Methylation><Methyltransferase><Mice><Mice Mammals><Modern Man><Modification Methylases><Molecular><Murine><Mus><Mutation><Nephropathy><Null Mouse><Oncoprotein p53><P53><Patients><Phosphoprotein P53><Phosphoprotein pp53><Play><Polycystic Kidney><Polycystic Kidney Diseases><Process><Programmed Cell Death><Protein Gene Products><Protein TP53><RAFT1><RNA Expression><Regulation><Renal Cyst><Renal Disease><Repression><Role><SET Domain><STAT3><STAT3 gene><Sequence Alteration><Severity of illness><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site-Specific DNA-methyltransferase><System><TP53><TP53 gene><TRP53><Testing><Therapeutic><Tissue Growth><Tissues><Transcription><Tumor Protein p53><Tumor Protein p53 Gene><Up-Regulation><Upregulation><biological signal transduction><bisulfite sequencing><bisulfite-seq><chromatin immunoprecipitation-sequencing><ciliogenesis><cilium biogenesis><conditional knock-out><conditional knockout><demethylation><disease severity><entire genome><epigenetic regulation><epigenetically><full genome><genome mutation><genome wide analysis><genome wide studies><genome-wide analysis><genome-wide identification><genomic alteration><histone H3 methyltransferase><histone methylase><histone methylation><histone methyltransferase><human disease><human whole genome><in vivo><inhibitor><kidney disorder><mTOR><malignancy><mammalian target of rapamycin><methylase><methylation pattern><mouse model><murine model><mutant><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ontogeny><p53 Antigen><p53 Genes><p53 Tumor Suppressor><protein function><protein p53><recruit><renal><renal disorder><renal epithelium><social role><survivin><translational opportunities><translational potential><transmethylase><whole genome>