Dissociable roles for histone acetyltransferases p300 and PCAF in hippocampus and perirhinal cortex‐mediated object memory

The importance of histone acetylation for certain types of memory is now well established. However, the specific contributions of the various histone acetyltransferases to distinct memory functions remain to be determined; therefore, we employed selective histone acetyltransferase protein inhibitors and short‐interference RNAs to evaluate the roles of CREB‐binding protein (CBP), E1A‐binding protein (p300) and p300/CBP‐associated factor (PCAF) in hippocampus and perirhinal cortex (PRh)‐mediated object memory. Rats were tested for short‐ (STM) and long‐term memory (LTM) in the object‐in‐place task, which relies on the hippocampus and PRh for spatial memory and object identity processing, respectively. Selective inhibition of these histone acetyltransferases by small‐interfering RNA and pharmacological inhibitors targeting the HAT domain produced dissociable effects. In the hippocampus, CBP or p300 inhibition impaired long‐term but not short‐term object memory, while inhibition of PCAF impaired memory at both delays. In PRh, HAT inhibition did not impair STM, and only CBP and PCAF inhibition disrupted LTM; p300 inhibition had no effects. Messenger RNA analyses revealed findings consistent with the pattern of behavioral effects, as all three enzymes were upregulated in the hippocampus (dentate gyrus) following learning, whereas only CBP and PCAF were upregulated in PRh. These results demonstrate, for the first time, the necessity of histone acetyltransferase activity for PRh‐mediated object memory and indicate that the specific mnemonic roles of distinctive histone acetyltransferases can be dissociated according to specific brain regions and memory timeframe.     

Improved inhibition of the histone acetyltransferase PCAF by an anacardic acid derivative

Several lines of evidence indicate that histone acetyltransferases (HATs) are novel drug targets for treatment of diseases like, for example, cancer and inflammation. The natural product anacardic acid is a starting point for development of small molecule inhibitors of the histone acetyltransferase (HAT) p300/CBP associated factor (PCAF). In order to optimize the inhibitory potency, a binding model for PCAF inhibition by anacardic acid was proposed and new anacardic acid derivatives were designed. Ten new derivatives were synthesized using a novel synthetic route. One compound showed a twofold improved inhibitory potency for the PCAF HAT activity and a twofold improved inhibition of histone acetylation in HEP G2 cells.     

Stimulation of DNA replication from the polyomavirus origin by PCAF and GCN5 acetyltransferases: acetylation of large T antigen

The PCAF and GCN5 acetyltransferases, but not p300 or CBP, stimulate DNA replication when tethered near the polyomavirus origin. Replication stimulation by PCAF and GCN5 is blocked by mutational inactivation of their acetyltransferase domains but not by deletion of sequences that bind p300 or CBP. Acetylation of histones near the polyomavirus origin assembled into chromatin in vivo is not detectably altered by expression of these acetyltransferases. PCAF and GCN5 interact with polyomavirus large T antigen in vivo, PCAF acetylates large T antigen in vitro, and large T-antigen acetylation in vivo is dependent upon the integrity of the PCAF acetyltransferase domain. These data suggest replication stimulation occurs through recruitment of large T antigen to the origin and acetylation by PCAF or GCN5.     

p300/CBP及其相关因子PCAF与转录调控

p300/CBP及相关因子PCAF具有乙酰转移酶活性,能通过乙酰化组蛋白和非组蛋白的方式参与基因的转录调控.同时,它们能在转录因子和基本转录复合物之间起到桥梁作用,而且也能为整合多种转录因子提供支架,是一种典型的转录辅激活子. p300/CBP与细胞周期调控、细胞凋亡以及癌症的发生等过程之间有着直接的联系。本文概括了p300/CBP与PCAF的基本特性,并简要介绍它们与其他蛋白之间的相互作用,特别是E1A的最新研究进展。