# Mechanisms of heterochromatin targeting and epigenetic genome regulation

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2020 · $376,858

## Abstract

PROJECT SUMMARY
 The long-term goals of this research program are to determine at a molecular level how long noncoding
RNAs (lncRNAs) participate in chromatin-mediated gene silencing. Many lncRNAs act in the nucleus to
regulate gene expression through scaffolding of chromatin regulatory machinery. The identification of lncRNAs
far outpaces detailed investigations, hence the mechanisms that govern these lncRNA-mediated events are
not yet well-understood. We will address four major outstanding questions in the field: 1) How do lncRNAs
target specific regions of the genome? 2) Do lncRNAs require structural remodeling for activation of chromatin
repression machinery? 3) How can a lncRNA contribute to halting gene transcription? 4) What is the full-extent
that a lncRNA can scaffold protein interactions on chromatin? Our immediate goals are to focus on the model
lncRNA HOTAIR while longer-term goals will investigate additional lncRNAs for which much less is known.
HOTAIR is transcribed from one developmentally-regulated HOX gene cluster and regulates many genes in
trans through the Polycomb silencing complex PRC2. Our recent progress has identified a new key player in
dictating the specificity of HOTAIR function and has suggested a model where HOTAIR uses a protein
"matchmaker" to mediate RNA-RNA base-pairing interactions with the nascent transcripts of target genes. We
will approach this model using the questions framed above to uncover a new level of mechanistic detail for this
lncRNA. A multi-faceted approach will be used, merging biochemical reconstitution with cutting edge
proteomics and genomics, to uncover how lncRNAs use their reservoirs of RNA sequence information to target
and scaffold heterochromatin formation. These studies will generate a model for lncRNA mechanism in gene
regulation that may be broadly applicable to other lncRNA pathways. We will also highlight potential molecular
targets to disrupt the HOTAIR activity that promotes metastasis in many cancers.
Relevance to public health
Long noncoding RNAs are produced from regions of the human genome originally thought to be "junk" DNA.
Many lncRNAs participate in epigenetic mechanisms of gene regulation and mis-regulation can lead to
diseases such as cancer. LncRNAs 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:** 9938625
- **Project number:** 5R35GM119575-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Aaron M. Johnson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,858
- **Award type:** 5
- **Project period:** 2016-08-16 → 2022-01-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938625

## Citation

> US National Institutes of Health, RePORTER application 9938625, Mechanisms of heterochromatin targeting and epigenetic genome regulation (5R35GM119575-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9938625. Licensed CC0.

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