# The crosstalk of DNA and lysine methyltransferases in ADPKD.

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $484,331

## Abstract

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.

## Key facts

- **NIH application ID:** 10092241
- **Project number:** 1R01DK126662-01
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Xiaogang Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $484,331
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092241

## Citation

> US National Institutes of Health, RePORTER application 10092241, The crosstalk of DNA and lysine methyltransferases in ADPKD. (1R01DK126662-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10092241. Licensed CC0.

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