Gene-specific transcription factors initiate transcription by specifically recognizing promoter regions of the target genes and mediating interactions with coregulators to recruit the remainder of the main transcriptional machinery. A large number of Mendelian human diseases have been linked to the mutations in genes encoding these transcription factors and in fact, a recent complete human genome analysis revealed that transcription factors represent one of the four major functional groups of proteins whose germline mutations result in various human diseases. Our long-term goal is to understand the molecular mechanisms of gene regulation by these transcription factors and the molecular basis of disease-causing mutations found in them, and this proposal focuses on diabetes. HNF1alpha and HNF4alpha play vital roles in organ development and adult homeostasis, and have been identified as culprit gene products for the monogenic dominant inherited forms of diabetes. Despite their similar physiological roles, they belong to completely different transcription factor families and possess distinctive mechanisms of gene regulation through their unique structures and interacting with different sets of coregulators. Detailed structural information on how the molecular interactions occur during the multicomplex formation is not completely known. Therefore, we propose to (1) solve the crystal structure of HNF1alpha and HNF4alpha in complex with its target DNA and other functional partners, and (2) examine the effects of diabetes-causing mutations on protein stability, DNA binding, protein-protein interaction in vitro and overall transcriptional activity in vivo to understand the molecular basis of gene regulation, complex formation and functional loss by mutations. These findings should aid overall understanding of transcription control involved in insulin action and secretion, and rational targeting of these transcription factors in order to modulate their activities and reverse the adverse effects by the mutations, thus potential treatment for diabetes.
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