Cis-regulatory circuitry underlying hedgehog mediated limb development

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Abstract: 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.