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A. K. Hennig, H. Wang, S. Chen; Histone Acetyltransferases CBP and p300 Are Required in Rod Photoreceptors to Maintain Retina Structure and Function. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1085.
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In retinal photoreceptors, the cone-rod homeobox transcription factor CRX recruits histone acetyltransferases (HATs) CBP (KAT3A) and p300 (KAT3B) to target gene promoters during transcription activation. To determine the roles of these transcription coactivators in maintaining photoreceptor function, we have conditionally knocked out these HATs in rod photoreceptors using Rhodopsin-Cre-mediated flox allele excision, and examined the consequences for retinal structure and function.
Mice carrying a Cre transgene driven by a 4-kb Rhodopsin promoter fragment were crossed with mice carrying floxed alleles of Cbp, p300, or both. Electroretinography (ERG), histopathology and immunohistochemistry were performed at various ages to assess retinal abnormalities and determine the time course of pathogenesis. Cell proliferation and apoptosis were monitored using cell-cycle specific markers and TUNEL assays.
Knockout of either Cbp or p300 in rods produces few abnormalities, but knockout of both results in gross disruption of the outer retina beginning at P10, with formation of whorls and rosettes in the outer nuclear layer (ONL). The outer plexiform and inner nuclear layers are also disordered, with wedges of protein kinase C alpha-positive cells extending into the ONL. No abnormal proliferation is seen. Around P14 the cells of the ONL lose their characteristic chromatin condensation and expression of photoreceptor markers, but do not die. Whorls and rosettes persist throughout life. Both dark- and light-adapted ERG are severely decreased by 4 weeks of age; the effects on cone function are likely due to physical disruption of the ONL. A single copy of p300 fully restores retinal architecture, but a single copy of Cbp is less effective, leading to minor irregularities in the ONL that persist to 12 weeks of age. Rod ERGs are slightly decreased in mice with a single copy of either HAT.
CBP and p300 have overlapping and distinct functions in maintaining retinal architecture and rod photoreceptor function. While both HATs are important, p300 appears to be more crucial for maintaining retina integrity.
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