Transcription Induction Integrated By Nuclear Receptor Coregulators

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.