# Mechanistic Insights into Mammalian DNA Methylation

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2021 · $459,688

## Abstract

Mechanistic Insights into Mammalian DNA Methylation
ABSTRACT
DNA methylation in mammals is a major epigenetic mechanism that is essential for transcriptional silencing of
retrotransposons, genomic imprinting, and X-chromosome inactivation. Aberrant DNA methylation leads to
genomic and chromosomal instabilities and silencing of tumor suppressor genes, which contribute to the
development of cancers and many other human diseases. Mammalian DNA methylation is established and
maintained by two groups of DNA methyltransferases (DNMTs): de novo DNMTs (DNMT3A and DNMT3B),
which are responsible for establishing the DNA methylation patterns during gametogenesis and early
embryogenesis, and maintenance DNMT (DNMT1), which propagates DNA methylation during mitotic division.
We have a long-standing interest in mechanistic understanding of mammalian DNA methylation, which has led
us to unravel the molecular basis of DNMT1-mediated maintenance DNA methylation and DNMT3A/3B-
mediated de novo DNA methylation. The activities of these DNMTs are governed not only by their intrinsic
enzymatic specificities, but also by an intricate network of cellular factors, such as histone modifications and
chromatin modifiers. However, the mechanism underlying the functional regulation of the DNA methylation
machinery remains poorly understood, partly due to the lack of structural and dynamic information on DNMTs
under the chromatin environment. Our research program focuses on addressing this important challenge
through an approach that integrates structural biology with biochemistry, molecular biology, and cell biology.
We have two long-terms goals: to provide a comprehensive understanding of the structure and mechanism of
DNA methylation machinery, and to identify the relationship between DNA methylation, gene regulation, and
human diseases. Our work in the past has led to structure-function understanding of the protein-protein and
protein-DNA interactions underpinning discrete steps of mammalian DNA methylation. We have identified
multilayered mechanisms, involving intricate interplay between intramolecular and intermolecular interactions,
for the substrate specificity and chromatin association of both maintenance and de novo DNA methylation
machinery. Our goal in the next five years is to gain a mechanistic understanding of mammalian DNA
methylation at the chromatin level, with emphasis on four new directions: (i) structural understanding of
mammalian DNA methylation in the chromatin context, (ii) dynamic characterization of mammalian DNA
methylation, (iii) protein engineering targeting specific DNA methylation pathways, and (iv) deciphering the
regulatory network of mammalian DNA methylation. Together, these combined studies promise to lead us
toward a comprehensive mechanistic understanding of mammalian DNA methylation.

## Key facts

- **NIH application ID:** 10167296
- **Project number:** 2R35GM119721-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Jikui Song
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $459,688
- **Award type:** 2
- **Project period:** 2016-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167296

## Citation

> US National Institutes of Health, RePORTER application 10167296, Mechanistic Insights into Mammalian DNA Methylation (2R35GM119721-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10167296. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*