Transcription coactivators p 300 and CBP are necessary for photoreceptor-specific chromatin organization and gene expression

Rod and cone photoreceptor neurons in the mammalian retina possess specialized cellular architecture and functional features for converting light to a neuronal signal. Establishing and maintaining these characteristics requires appropriate expression of a specific set of genes, which is tightly regulated by a network of photoreceptor transcription factors centered on the cone-rod homeobox protein CRX. CRX recruits transcription coactivators p300 and CBP to acetylate promoter-bound histones and activate transcription of target genes. To further elucidate the role of these two coactivators, we conditionally knocked out Ep300 and/or CrebBP in differentiating rods or cones, using opsin-driven Cre recombinase. Knockout of either factor alone exerted minimal effects, but loss of both factors severely disrupted target cell morphology and function: the unique nuclear chromatin organization seen in mouse rods was reversed, accompanied by redistribution of nuclear territories associated with repressive and active histone marks. Transcription of many genes including CRX targets was severely impaired, correlating with reduced histone H3/H4 acetylation (the products of p300/CBP) on target gene promoters. Interestingly, the presence of a single wild-type allele of either coactivator prevented many of these defects, with Ep300 more effective than Cbp. These results suggest that p300 and CBP play essential roles in maintaining photoreceptor-specific structure, function and gene expression. Citation: Hennig AK, Peng G-H, Chen S (2013) Transcription Coactivators p300 and CBP Are Necessary for Photoreceptor-Specific Chromatin Organization and Gene Expression. PLoS ONE 8(7): e69721. doi:10.1371/journal.pone. 0069721 Editor: Thomas Langmann, University of Cologne, Germany Received January 15, 2013; Accepted June 12, 2013; Published July 26, 2013 Copyright: 2013 Hennig et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National Institutes of Health (NIH) [grant numbers EY012543 to SC and EY02687 to WU-DOVS], a Lew Wasserman Merit Award (to SC) and unrestricted funds (to WU-DOVS) from Research to Prevent Blindness. For use of the electron microscope: the Research Center for Auditory and Vestibular Studies is supported by the National Institutes of Health NIDCD Grant P30DC04665 to the Department of Otolaryngology. For genomic analysis: the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine is partially supported by the National Institutes of Health [National Cancer Institute Cancer Center Support grant number P30 CA91842 to the Siteman Cancer Center; National Center for Research Resources (NCRR) ICTS/CTSA grant number UL1RR024992; and the NIH Roadmap for Medical Research]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: chen@vision.wustl. edu ¤ Current address: Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China