# Defining the epigenetic mechanisms underlying GLI-mediated transcriptional repression

> **NIH NIH F31** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $15,678

## Abstract

PROJECT SUMMARY
The Sonic hedgehog (SHH) pathway is necessary for multiple steps of craniofacial development. Mutations in
this pathway lead to devastating birth defects including holoprosencephaly and Pallister-Hall syndrome.
Furthermore, a spectrum of diseases collectively referred to as craniofacial ciliopathies, are caused by ciliary
mutations that affect the processing of GLI proteins, the transcriptional effectors of the pathway. This disruption
in processing often leads to a reduction in both GLI activator (GLI-A) and GLI repressor (GLI-R). While GLI-A is
necessary for activation of several transcriptional SHH targets, most genes are in fact activated by the de-
repression of GLI-R. Despite a clear genetic requirement for GLI-R in craniofacial development, the
mechanisms by which it elicits repression are undefined. This proposal aims to fill a fundamental gap in our
understanding of how GLI-R proteins maintain transcriptional repression during craniofacial development.
Specifically, I seek to determine if GLI repression regulates transcription by regulating epigenetic markers and
by physically altering chromatin structure in terms of chromatin accessibility and GLI enhancer-promoter
interactions. I hypothesize that GLI-R recruits HDACs to maintain GLI enhancers in an epigenetically
repressed state with restricted chromatin accessibility and prevents GLI enhancer-promoter interactions from
being established. The experiments in this proposal will provide direct mechanistic insight into the processes
underlying the transcriptional regulation of SHH target genes. By identifying GLI-bound enhancers regulated by
SHH signaling in craniofacial patterning, it will also serve as a resource for other scientists studying SHH
regulation.
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## Key facts

- **NIH application ID:** 10192495
- **Project number:** 5F31DE027597-04
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Rachel K Lex
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $15,678
- **Award type:** 5
- **Project period:** 2017-09-01 → 2021-01-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10192495

## Citation

> US National Institutes of Health, RePORTER application 10192495, Defining the epigenetic mechanisms underlying GLI-mediated transcriptional repression (5F31DE027597-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10192495. Licensed CC0.

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