# Investigating histone glycation as a new dynamic epigenetic mark

> **NIH NIH R35** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $439,201

## Abstract

Project Summary
The past decade has witnessed explosive advances in our understanding of how the organization of
chromatin controls gene expression in eukaryotes. Much of the work delineating these mechanisms has
contributed to the notion that a so-called ‘Histone Code,’ which refers to the landscape of histone post-
translational modifications (PTMs), is a central determinant of a gene's potential to be activated or
repressed in response to environmental stimuli. However, although detected in vivo, very little is known
about how non-enzymatic covalent modifications (NECMs), such as glycation, affect the established
cellular transcriptional program. We recently found that glycation, which is the hallmark of diabetes,
accumulates on histones in a disease state-dependent manner (Zheng et al. Nature Communications,
2019). Using a variety of biophysical, biochemical and genetic methods we found that histone glycation
disrupts regulatory histone PTMs as well as changes chromatin architecture in vitro and in cells by forming
both histone-histone and histone-DNA crosslinks. Importantly, we identified a cellular regulatory response
to this damage in the form of the deglycase DJ-1 as well as more recently, an arginine-specific deglycase,
PAD4, which further demonstrates the crosstalk between histone glycation and other enzymatic PTMs
(Zheng et al., in revision). In this proposal, we will take an interdisciplinary approach and leverage new
chemical probes we developed to determine the sites of glycation on histones and their distribution within
chromatin. In addition, we will perform a high-resolution analysis to identify the precise mechanistic effect
histone glycation has on higher-order chromatin structure and the epigenetic landscape. Finally, we will
investigate the cellular response to glycation by identifying “readers” and “erasers” of this new mark.
Successful completion of this project is expected to yield a detailed molecular mechanism linking a new
class of histone modifications to transcription regulation, thus providing essential insights into a
fundamental biological problem and opening the door to new therapeutic avenues.

## Key facts

- **NIH application ID:** 10029205
- **Project number:** 1R35GM138386-01
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Yael E David-Shternberg
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $439,201
- **Award type:** 1
- **Project period:** 2020-07-10 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029205

## Citation

> US National Institutes of Health, RePORTER application 10029205, Investigating histone glycation as a new dynamic epigenetic mark (1R35GM138386-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10029205. Licensed CC0.

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