Mammalian Gene Expression Program Resiliency: The Roles of Multiple Coactivator Mechanisms in Hypoxia-Responsive Transcription

CBP and its paralog p300 (CBP/p300 collectively) are transcriptionalcoactivators that are among the most interconnected proteins in the mammalian proteinprotein"interactome", with over 315 described interaction partners. CBP/p300 areprotein/histone acetyltransferases, but most of the protein-binding domains ofCBP/p300 are unique to these two coactivators, indicating that CBP/p300 should behighly limiting. The CH1 domain of CBP/p300 was considered essential for most, if notall, hypoxia-inducible transcription by binding to hypoxia-inducible-factor-1? (HIF-1?).Mutating CH1 had little effect, however, on the hypoxia-induced transcription of the HIFtargetgenes Higd1a, Egln1 (prolyl-hydroxylase), Bnip3 (Bcl2-interacting-protein-3), andPfkl (phosphofructokinase). In contrast, HIF-targets Pgf (placental growth factor) andEgln3 were strongly affected by the CH1 mutation, while Stc1 (stanniocalcin-1) andSlc2a1 (glucose-transporter-1) were moderately affected. HIF targets were alsodependent on coactivation mechanisms that are sensitive to trichostatin A (TSAS).Paradoxically, TSA inhibits histone deacetylases (HDACs) that are usually associatedwith transcriptional repression, implying that HDACs can also function as coactivators.Thus, activator-specific transcription in mammals requires seemingly unrelatedcoactivator mechanisms, and individual target genes vary in their requirements for eachmechanism. Gene expression program resiliency is therefore coupled with gene specificregulation by avoiding uniform reliance on a "keystone" coactivator interaction.