# Epigenetic Mechanisms of Retrotransposon Silencing

> **NIH NIH R35** · VAN ANDEL RESEARCH INSTITUTE · 2024 · $475,000

## Abstract

Project Summary/Abstract
Retrotransposons are ancient components of our genetic code that have self-replicated over millions of years
and now make up 45% of our genome. Retrotransposon activation has serious implications for cell viability –
retrotransposition is mutagenic by its nature and even expression of “dead” retrotransposons can trigger innate
immune responses that cause inflammation. Therefore, the cell has evolved intricate epigenetic mechanisms
to silence expression of retrotransposons by sequestering them in constitutive heterochromatin, which is
marked the epigenetic modifications of H3K9 methylation and DNA CpG methylation. Dysregulation of H3K9
methylation and CpG methylation causes widespread re-activation of retrotransposons and occurs in multiple
human diseases. However, very little is known about the precise molecular mechanisms that initiate
retrotransposon silencing or maintain retrotransposons in a silent state. The broad goal of this research
program is to define the precise molecular mechanisms the cell uses to suppress retrotransposon
expression. A key component of the cells retrotransposon silencing machinery is the histone lysine
methyltransferase Setdb-1, which deposits H3K9 methyl marks at retrotransposons. Because of its central role,
Setdb-1 activity is tightly regulated by a complex cast of molecular players that control its catalytic activation,
recruitment to retrotransposon sequences and its ability to spread histone methylation across the length of
retrotransposons. Appropriate control of Setdb-1 activity is critical for retrotransposon silencing, but many
aspects of Setdb-1 regulation remain enigmatic. We will use in vitro biochemical reconstitutions, Cryo-EM
and genomics to decipher the precise mechanisms that underly regulation of Setbd-1. The work outlined
in this proposal will explain how Setdb-1 is catalytically activated for retrotransposon silencing, how Setdb-1
reads the epigenetic code on retrotransposons and how Setdb-1 is recruited to retrotransposon sequences to
establish H3K9 methylation patterns.

## Key facts

- **NIH application ID:** 10928090
- **Project number:** 5R35GM147261-03
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Evan J Worden
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $475,000
- **Award type:** 5
- **Project period:** 2022-09-09 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928090

## Citation

> US National Institutes of Health, RePORTER application 10928090, Epigenetic Mechanisms of Retrotransposon Silencing (5R35GM147261-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10928090. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*