Is histone acetylation the most important physiological function for CBP and p300?

Abstract

Protein lysine acetyltransferases (HATs or PATs) acetylate histones and other proteins, and are principally modeled as transcriptional coactivators. CREB binding protein (CBP, CREBBP) and its paralog p300 (EP300) constitute the KAT3 family of HATs in mammals, which has mostly unique sequence identity compared to other HAT families. Although studies in yeast show that many histone mutations cause modest or specific phenotypes, similar studies are impractical in mammals and it remains uncertain if histone acetylation is the primary physiological function for CBP/p300. Nonetheless, CBP and p300 mutations in humans and mice show that these coactivators have important roles in development, physiology, and disease, possibly because CBP and p300 act as network "hubs" with more than 400 described protein interaction partners. Analysis of CBP and p300 mutant mouse fibroblasts reveals CBP/p300 are together chiefly responsible for the global acetylation of histone H3 residues K18 and K27, and contribute to other locus-specific histone acetylation events. CBP/p300 can also be important for transcription, but the recruitment of CBP/p300 and their associated histone acetylation marks do not absolutely correlate with a requirement for gene activation. Rather, it appears that target gene context (e.g. DNA sequence) influences the extent to which CBP and p300 are necessary for transcription.

Figure 1

The relative location of conserved domains in CBP and p300. NRID (nuclear receptor interaction domain), CH1 (cysteine/histidine-rich region 1, also known as transcriptional-adaptor zinc-finger domain 1 or TAZ1), KIX (kinase inducible domain of CREB interacting domain), Bromodomain (Br), PHD (plant homeodomain), HAT (histone acetyltransferase domain), ZZ (ZZ-type zinc finger domain), TAZ2 (transcriptional-adaptor zinc-finger domain 2; ZZ and TAZ2 together are sometimes referred to as CH3 or cysteine/histidine-rich region 3), and NCBD [nuclear coactivator binding domain or IRF3-binding domain (IBiD)] [26,27,86]. Regions in black indicate the largely nonconserved and unstructured sequences between the conserved domains (white boxes). Locations of Ser436 (Ser437 in humans) in the mouse CBP CH1 domain and Gly422 (Gly421 in humans) in the corresponding position of p300 are indicated. Not drawn to scale.

Figure 2

The “coactivator-poor and coactivator-rich” model showing that increased recruitment of distinct classes of coactivators (HATs CBP/p300, and non-HATs CRTC) at promoters with more bound transcription factor (CREB bound to cAMP response elements) may increase transcriptional resilience at certain endogenous target genes. Broadness of the curved arrows indicates the amount of different types (colored) of transactivating “biochemical flux” that stimulate transcription. In certain endogenous promoter contexts the increased flux though one mechanism (e.g. CRTC) may overcome the lack of a different mechanism (e.g. CBP/p300) [41]. Other types of coactivators (“x”) that might be present and participate in gene activation are shown.