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Transcription Induction Integrated by Nuclear Receptor Coregulators
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Studies carried out during the past decade have §shown that transcription of inducible §eukaryotic genes involves sequential chromatin §modifications by promoter-specific transcription §factors and a class of proteins called transcription §coregulators. First, this work identifed §important chromatin modifications and modifying §complexes at the CYP17 transcription start site and §nearby steroidogenic factor-1 (SF-1) binding site. §Post translational modifications (PTMs) to SF-1 also §occur as this transcription factor interacts with §the promoter. In addition, ACTH/cAMP signaling in §adrenal cortex alters SF-1-containing chromatin-§modifying complexes during the early phase of §transcriptional induction of CYP17. Chromatin §IP (ChIP) and mammalian two hybrid experiments §identified complexes which are cAMP-inducible, but §sensitive to the SF-1 antagonist sphingosine. SF-1 §PTMs at the ligand binding pocket opening were found §to be required for CYP17 transcription. Last, §certain corepressors are protein kinase A §(PKA) targets and are functionally sensitive to PKA-§dependent NADH accumulation. Thus, signaling, §metabolism, and transcription are integrated.
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