# Mechanisms of heterochromatin targeting and epigenetic genome regulation

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2022 · $422,206

## Abstract

PROJECT SUMMARY
 Epigenetic gene repression by heterochromatin is necessary for multi-cellular organismal development
and genome stability. Mis-regulation of heterochromatin is a cause of multiple diseases through perturbed gene
expression patterns. The long-term goals of our research program are to determine at a molecular level how
noncoding RNAs (ncRNAs) participate in heterochromatin formation and function. Many ncRNAs act in the
nucleus to regulate gene expression through association with chromatin regulatory machinery. We and others
have shown that certain RNA-mediated heterochromatin pathways require intermolecular RNA-RNA interactions
between ncRNAs and nascent RNA that serve as the trigger to form heterochromatin. However, many systems
where RNA is implicated have unexplored molecular mechanisms of action. We will address three high-level
major outstanding questions in the field: 1) Which heterochromatin systems are controlled through RNA-RNA
interactions? 2) How is heterochromatin built around nascent RNA? 3) How are RNA binding proteins re-
purposed from mRNA processing functions to contribute to RNA-mediated heterochromatin formation? Our
research program focuses on multiple heterochromatin systems that incorporate different species of noncoding
RNAs. We study long noncoding RNAs (lncRNAs), such as HOTAIR and pericentromeric transcripts, which can
inhibit heterochromatic histone modifiers to control their activity. In addition, we have developed the first
biochemical system to study the human nuclear piRNA pathway, which uses base-pairing of the small piRNA to
target nascent transcripts of repeats that then are suppressed via heterochromatin. Finally, we address how
RBPs such as the N6-methyladenosine reader YTHDC1 can work with ncRNAs to promote gene repression.
We use biochemical, structural, cell biological, and genomic approaches to study these models of RNA-regulated
heterochromatin. Mechanistic insight into these pathways will provide a fuller understanding of how they work
normally and in disease, which will prove useful in targeting for pharmacological intervention.
Relevance to public health
Noncoding RNAs are produced from regions of the human genome originally thought to be "junk" DNA. Many
ncRNAs participate in epigenetic mechanisms of gene regulation and mis-regulation can lead to diseases such
as cancer. ncRNAs are therefore clear candidates to provide a missing link to understanding the molecular
mechanisms of many human diseases for which there is a "hidden heritability" factor that has not yet been
identified.

## Key facts

- **NIH application ID:** 10337814
- **Project number:** 1R35GM144358-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Aaron M. Johnson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $422,206
- **Award type:** 1
- **Project period:** 2022-01-20 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337814

## Citation

> US National Institutes of Health, RePORTER application 10337814, Mechanisms of heterochromatin targeting and epigenetic genome regulation (1R35GM144358-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10337814. Licensed CC0.

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