Development and maintenance of rod and cone photoreceptors require coordinately regulated expression of photoreceptor genes. This regulation occurs at multiple levels and requires the action of a network of transcription regulatory proteins. This regulatory network is centered on the cone-rod homeobox protein CRX and incorporates both photoreceptor-specific transcription factors (TFs) and general chromatin modulators. The ultimate goal of our research is to determine how this regulatory protein network interacts with the chromatin of co-expressed target genes to achieve coordinately regulated spatial and temporal expression, providing a better understanding of photoreceptor development and disease. During the last grant period, we discovered that CRX regulates target gene chromatin configurations by recruiting co-activators capable of catalyzing acetylation of histones and organizing intra-gene interactions between regulatory regions. In the new grant period, we will extend our vision of transcriptional regulation to three dimensions: We hypothesize that rod and cone genes are co-regulated as clusters, requiring appropriate higher-order chromosome organization in the nucleus that is mediated by specific TFs and general epigenetic modulators. To test this hypothesis, Aim 1 will determine the role of histone H3 lysine 4 methylation, a positive mark that occurs downstream of acetylation, by assessing the effects of deleting three catalytic enzymes, MLL1, MLL2 and MLL3 in rods, cones and their precursors;
Aim 2 will reveal specific intra- and inter-chromosome interactions of co-regulated photoreceptor genes and their co-localization in rod vs. cone nuclei using state-of-the-art epigenetic technologies. To determine if these chromosome organizations contribute to transcription co-regulation during subtype specification and maintenance, profiles of chromosome interactions, TF binding, histone marks and transcription will be studied at various developmental ages. We will also determine if the transcription regulatory network mediates the specific chromosome interactions by analyzing mutant retinas lacking specific TFs or epigenetic modulators. This study will provide the first targeted assessment of transcriptional co-regulation of photoreceptor genes and determine the underlying molecular and cellular mechanisms. The new knowledge gained will have implications in developing stem cell-based cell replacement therapy as well as providing new targets for other therapeutic interventions.
The expression of rod and cone genes is coordinately regulated by an intrinsic program established by two types of transcription regulators: photoreceptor-specific transcription factors and general epigenetic modulators. This study investigates the mechanism of action of this program using multi-disciplinary genomics technologies, addressing the importance of each type of transcription regulator in establishing transcription patterns and yielding a three-dimensional view of transcriptional regulation within photoreceptor nuclei. Together, these will provide insights into the intrinsic program governing photoreceptor development and maintenance. We expect these novel approaches to advance our understanding of photoreceptor diseases and lead to new treatment strategies.
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|Masuda, Tomohiro; Zhang, Xiaodong; Berlinicke, Cindy et al. (2014) The transcription factor GTF2IRD1 regulates the topology and function of photoreceptors by modulating photoreceptor gene expression across the retina. J Neurosci 34:15356-68|
|Tran, Nicholas M; Chen, Shiming (2014) Mechanisms of blindness: animal models provide insight into distinct CRX-associated retinopathies. Dev Dyn 243:1153-66|
|Hennig, Anne K; Peng, Guang-Hua; Chen, Shiming (2013) Transcription coactivators p300 and CBP are necessary for photoreceptor-specific chromatin organization and gene expression. PLoS One 8:e69721|
|Peng, Guang-Hua; Chen, Shiming (2013) Double chromatin immunoprecipitation: analysis of target co-occupancy of retinal transcription factors. Methods Mol Biol 935:311-28|
|Peng, Guang-Hua; Chen, Shiming (2011) Active opsin loci adopt intrachromosomal loops that depend on the photoreceptor transcription factor network. Proc Natl Acad Sci U S A 108:17821-6|
|Wang, Qing; Song, Sheng-Kwei; Zhang, Huiying et al. (2011) Photoreceptor degeneration changes magnetic resonance imaging features in a mouse model of retinitis pigmentosa. Magn Reson Med 65:1793-8|
|de Melo, Jimmy; Peng, Guang-Hua; Chen, Shiming et al. (2011) The Spalt family transcription factor Sall3 regulates the development of cone photoreceptors and retinal horizontal interneurons. Development 138:2325-36|
|Onishi, Akishi; Peng, Guang-Hua; Chen, Shiming et al. (2010) Pias3-dependent SUMOylation controls mammalian cone photoreceptor differentiation. Nat Neurosci 13:1059-65|
|Onishi, Akishi; Peng, Guang-Hua; Poth, Erin M et al. (2010) The orphan nuclear hormone receptor ERRbeta controls rod photoreceptor survival. Proc Natl Acad Sci U S A 107:11579-84|
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