Transcription coactivators p300 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.
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Anne K
AK
Hennig
Guang-Hua
GH
Peng
Shiming
S
Chen
D000107:Acetylation; D000375:Aging / Q000473:pathology; D000818:Animals; D002843:Chromatin / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D005786:Gene Expression Regulation; D006579:Heterozygote; D006657:Histones / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
D002843:Chromatin; D006657:Histones; D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D015534:Trans-Activators; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse