Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases

Abstract

One general principle of gene regulation is that DNA-binding transcription factors modulate transcription by recruiting cofactors that modify histones and chromatin structure. A second implicit principle is that a particular cofactor is necessary at all the target genes where the cofactor is recruited. Increasingly, these principles do not appear to be absolute, as experimentally defined relationships between transcription, cofactors and chromatin modification grow in complexity. The KAT3 histone acetyltransferases CREB binding protein (CBP) and p300 have at least 400 interacting protein partners, thereby acting as hubs in gene regulatory networks. Studies using mutant primary cells indicate that the occurrence of CBP and p300 at any given target gene sometimes correlates with, rather than dictates transcription. This suggests that there are unexpected levels of redundancy between CBP/p300 and other unrelated coactivators, or that CBP/p300 recruitment may sometimes be coincidental. A transcription factor may therefore recruit the same group of coactivators as part of its "toolbox", but it is the characteristics of the individual target gene that determine which coactivation "tools" are required for its transcription.

Figure 1

Phylogram of 20 mammalian HAT proteins by clustalW sequence alignment and their KAT nomenclature. Shaded boxes indicate the gene families as defined by Ensembl. Reported lethality phenotypes are indicated for individual gene knockout mouse models and where possible for multi-gene family knockouts. * 2/3 of mice die by 1 month of age. **Increased mortality throughout lifespan.

Figure 2

CBP and p300 are closely related HATs that possess unique protein binding domains. Principal protein-binding domains of CBP and p300: nuclear receptor interaction domain (RID), the Cys/His-rich region 1 (CH1), the CREB-binding domain (KIX), bromodomain (Br), plant homeodomain (PHD), histone acetyltransferase domain (HAT), zinc-binding domain near the dystrophin WW domain (ZZ), the Cys/His-rich region 3 (CH3), and the interferon response factor-binding domain (IBiD).