The Hedgehog (Hh) signaling pathway is a major regulator of organ development that utilizes the primary cilium to regulate its transcriptional output through the GLI transcription factors. The effects of Hh signaling are primarily mediated through de-repression of GLI target genes, which in the absence of Hh inhibit transcription through an unknown mechanism. This proposal seeks to understand how GLI repressors regulate Hedgehog signaling in normal development and how this is altered in ciliopathies. We hypothesize that GLI repressors inhibit gene expression by regulating chromatin modifications at enhancers. We will determine if GLI repression occurs through the recruitment of a Histone deacetylase complex. We will also establish when GLI enhancers first acquire accessible chromatin and if their interactions with promoters require Hh signaling. We further hypothesize that GLI proteins repress enhancer activity prior to Hh activation. By testing this, we will provide the first detailed information about the early Hh morphogen response and determine if GLI transcriptional dynamics are altered in a mouse model of human ciliopathies. Collectively, these aims will provide key insights into the processes and temporal dynamics by which GLI proteins interact with and regulate chromatin to repress transcription. In addition, they will determine how GLI transcriptional networks are first established and altered in ciliopathies, providing insight into how GLI dysregulation causes structural birth defects in these syndromes.

Public Health Relevance

Defects in the Hedgehog signaling pathway underlie a vast spectrum of human birth defects, including ciliopathies, holoprosencephaly, cleft palate, and a variety of limb defects such as polydactyly. This proposal seeks to fill a fundamental gap in our understanding of Hh signaling regulates gene expression through the GLI proteins. It will determine how GLI proteins interface with chromatin to regulate gene expression and how transcriptional networks are altered in ciliopathies, providing insight on how GLI dysregulation causes structural birth defects in these syndromes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD073151-06A1
Application #
9523593
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Toyama, Reiko
Project Start
2012-08-25
Project End
2023-06-30
Budget Start
2018-08-25
Budget End
2019-06-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759
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