# Defining the mechanisms of epigenetic information flow

> **NIH NIH R35** · UNIVERSITY OF CHICAGO · 2022 · $411,040

## Abstract

Chromatin, the assemblage of protein, DNA and RNA that represents the physiologic
form of the eukaryotic genome, imposes a million-fold length-scale compaction to fit
DNA in the nucleus. Rather than serving as mere static packaging, chromatin structure
acts as a dynamic regulator of underlying DNA function. Local chromatin structure may
be stable for decades, yet is sufficiently dynamic to respond to signaling pathways,
potentiating transcriptional program changes in development, disease, and
environmental changes. Indeed, cellular identity and changes thereof are intimately
connected to chromatin states-- keeping a neuron a neuron and not a liver cell. Apart
from DNA sequence-specific transcription factors, the information carriers responsible
for this structural variation are chemical modifications to the genome itself and attendant
histone proteins involved in packaging (often referred to as “epigenetic” marks), as well
as noncoding RNA acting at the chromatin interface. Although little known about these
epigenetic information carriers, it is clear that they play crucial roles in development,
cognition and disease. Elucidation of the molecular mechanisms by which epigenetic
information carriers impact chromatin structure and function, particularly in the context
of transcriptional activation is the unifying theme of the Ruthenburg lab. In the next four
years, we will discover and characterize the detailed mechanisms of new epigenetic
information carriers, focusing on nucleosome-level variation and orphaned histone
modifications, defining binding partners for recently appreciated DNA modifications and
their function, and performing detailed mechanistic characterization of a class of
molecules we discovered--chromatin-enriched noncoding RNA that act as local
transcriptional activators. In addition, we will biochemically define the function of RNA in
the MLL/SET1 family of histone modification complexes and its functional
consequences in cellular contexts. Our interdisciplinary work in these areas will require
the development of new tools and experimental approaches—our outstanding track
record of pioneering tool development with NIGMS funding makes the case that future
efforts will meet with similar success. The fundamental mechanistic understanding of
epigenetic information systems we will develop through these avenues will impact our
understanding of nuclear function and its dysregulation in disease.

## Key facts

- **NIH application ID:** 10406734
- **Project number:** 1R35GM145373-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Alexander Jackson Ruthenburg
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $411,040
- **Award type:** 1
- **Project period:** 2022-09-08 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406734

## Citation

> US National Institutes of Health, RePORTER application 10406734, Defining the mechanisms of epigenetic information flow (1R35GM145373-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10406734. Licensed CC0.

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