Mechanisms underlying GLI mediated transcriptional regulation
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The Hedgehog signaling pathway is an evolutionarily conserved pathway that plays critical roles in both embryogenesis and adult tissue homeostasis. It has been extensively studied in fruit fly, zebra fish and mouse models. Dysregulation of Hedgehog signaling causes a wide range of birth defects, such as craniofacial defects, limb defects, and holoprosencephaly. Ectopic activation of Hedgehog signaling in adult tissues also gives rise to tumors, such as basal cell carcinoma in the skin and certain types of brain cancers. Precise control of gene transcription is regulated by both genomic cis-regulatory elements as well as protein co-factors. To understand how Hedgehog signaling mediates transcriptional regulation, I investigated both genomic cis-regulatory elements as well as protein co-factors. Using mouse genetic approaches, I characterized a GLI responsive cis-regulatory module, GRE1, and its role in Gremlin transcription regulation during limb development. I demonstrate that temporal and spatial controls of key developmental genes are mediated through comprehensive co-regulation of multiple cis-regulatory modules. In the second part of my study, I purified a GLI protein complex from embryonic stem (ES) cells and identified NANOG as a novel GLI-associated protein co-factor in ES cells. Further studies revealed that NANOG inhibits Hedgehog signaling-mediated transcription by interfering with GLI activities, providing a new mechanism of how NANOG protects ES cells from extracellular differentiation signals. I also applied and optimized the affinity-purification and mass spectrometry technique to small embryonic tissue samples, which would allow us to identify protein complexes in more relevant context.