Dynamic acetylation of all lysine-4 trimethylated histone H3 is evolutionarily conserved and mediated by p300/CBP

Abstract

Histone modifications are reported to show different behaviors, associations, and functions in different genomic niches and organisms. We show here that rapid, continuous turnover of acetylation specifically targeted to all K4-trimethylated H3 tails (H3K4me3), but not to bulk histone H3 or H3 carrying other methylated lysines, is a common uniform characteristic of chromatin biology in higher eukaryotes, being precisely conserved in human, mouse, and Drosophila. Furthermore, dynamic acetylation targeted to H3K4me3 is mediated by the same lysine acetyltransferase, p300/cAMP response element binding (CREB)-binding protein (CBP), in both mouse and fly cells. RNA interference or chemical inhibition of p300/CBP using a newly discovered small molecule inhibitor, C646, blocks dynamic acetylation of H3K4me3 globally in mouse and fly cells, and locally across the promoter and start-site of inducible genes in the mouse, thereby disrupting RNA polymerase II association and the activation of these genes. Thus, rapid dynamic acetylation of all H3K4me3 mediated by p300/CBP is a general, evolutionarily conserved phenomenon playing an essential role in the induction of immediate-early (IE) genes. These studies indicate a more global function of p300/CBP in mediating rapid turnover of acetylation of all H3K4me3 across the nuclei of higher eukaryotes, rather than a tight promoter-restricted function targeted by complex formation with specific transcription factors.histone acetylation turnover | Trichostatin A | p300/CBP inhibitor

Inositol polyphosphate multikinase is a transcriptional coactivator required for immediate early gene induction

“…IPMK regulates IEGs by binding to CBP to augment its recruitment to promoters of the IEGs. Because of the importance of CBP function and IEGs for plasticity of neuronal function (22,(26)(27)(28)(29)(30)(31)(32), we suggest that IPMK is a novel determinant of mechanisms underlying learning and memory. Such a possibility is supported by the impaired performance of nestin-Cre +/− IPMK fl/fl mice in contextual habituation and the Barnes maze test.…”

Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers

“…What are these pioneering factors? These recruitment events may lead to the methylation of H3K4 on the mutant allele, which in turn drives H3 acetylation (Crump et al 2011). Histone modifications such as these promote the transition of Pol II from an initiating form to an elongating form (Stasevich et al 2014), resulting in gene expression.…”

A Screen for X-Linked Mutations Affecting Drosophila Photoreceptor Differentiation Identifies Casein Kinase 1α as an Essential Negative Regulator of Wingless Signaling

“…CBP has been shown to potentiate MAPK-enhanced transcriptional activation by the Ets-2 transcription factor (Foulds et al 2004), but it is also important for Dpp, Hh, and Wg signaling in some contexts (Akimaru et al 1997;Waltzer and Bienz 1998;Waltzer and Bienz 1999;Li et al 2007). CBP functions as a histone acetyltransferase that acts on H3K27, H3K56, and trimethylated H3K4 (Das et al 2009;Tie et al 2009;Crump et al 2011). The specific effects of nej 8B27 suggest that acetylation of these histones is most critical for EGFR signaling during eye disc development.…”