# Molecular mechanisms of chromatin signaling and epigenetic regulation

> **NIH NIH R35** · VAN ANDEL RESEARCH INSTITUTE · 2024 · $518,400

## Abstract

PROJECT SUMMARY
DNA methylation and histone post-translational modifications (PTMs) are key epigenetic regulators of chromatin
accessibility, interaction, and function. Changes in the composition, abundance, and distribution of DNA
methylation and histone PTMs, and associated rearrangements in chromatin structure, are defining features of
human cancer and other diseases. While much progress has been made connecting epigenetic regulation to
cellular function and disease, it is still not clear how these regulatory functions are accomplished with spatial and
temporal precision, how these epigenetic signals translate to functional outcomes in chromatin regulation, and
how these changes contribute to disease states. Our long-term goal is to translate basic mechanistic
understanding of chromatin regulatory function into new strategies for the treatment of human diseases. Toward
this goal, we develop and use cutting edge biochemical, genomic, and proteomic technologies to understand the
interconnected molecular activities of chromatin regulatory proteins that “read,” “write,” and “erase” DNA
methylation and histone PTMs. Our past work focused on defining molecular mechanisms regulating the
epigenetic inheritance of DNA methylation through cell divisions. We revealed complex mechanisms involving
multivalent DNA and histone associations and allosteric regulation that influence DNA methyltransferase
chromatin targeting and substrate specificity. These studies also contributed to the appreciation that DNA
methyltransferases utilize ubiquitin-dependent protein interactions to facilitate their enzymatic activities, but the
mechanistic details of how DNA methylation and ubiquitin signaling interface are unclear. Our goals in the next
five years are to define regulatory and pathologic mechanisms that connect ubiquitin signaling to the epigenetic
inheritance of DNA methylation. Toward accomplishing these goals, we will study roles for protein ubiquitination
in big picture questions of: 1) how, when, and where DNA methylation regulators are targeted in the genome to
carry out their enzymatic functions; 2) how abnormal 5mC patterns arise in cancer and aging cells; and 3) how
these changes contribute to other molecular hallmarks of these disease and disease-associated states. To
facilitate these studies, we will also 4) develop a new class of ubiquitinated histone affinity reagents that is
generalizable for the enrichment of singly and combinatorially modified histone PTM states. Collectively, our
studies will continue to define fundamental mechanisms regulating DNA methylation inheritance, reveal
pathologic mechanisms associated with abnormal DNA methylation signaling, and introduce new reagents and
methods for this field.

## Key facts

- **NIH application ID:** 10765220
- **Project number:** 1R35GM152184-01
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Scott Rothbart
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $518,400
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765220

## Citation

> US National Institutes of Health, RePORTER application 10765220, Molecular mechanisms of chromatin signaling and epigenetic regulation (1R35GM152184-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10765220. Licensed CC0.

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