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Dissecting the biochemical role of epigenetically modified regulatory sequences within the genomes of retinal neurons (A1)

Award Number: R15EY028725
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract: Genomes acquire heritable and reversible chemical modifications that play a large role in influencing gene expression. These epigenetic modifications to the genome are fluid and often change allowing cells flexibility to alter patterns of gene expression based on environmental cues. 5- methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic modifications of DNA associated with transcriptional regulation in vertebrate genomes. Consortium projects such as the ENCODE Project and the Roadmap Epigenomics Project have demonstrated unique patterning of epigenetically modified DNA in the genomes of diverse cell and tissue types alluding to a critical role in cell fate differentiation and disease progression. Within the retina, differentiation and maintenance of photoreceptors relies on precise transcriptional regulation of complex gene networks associated with unique patterns of DNA methylation. However, mechanistic detail of how DNA methylation and demethylation contribute to retinal development and disease remains unclear. Our preliminary evidence suggests a role for DNA methylation in directly modulating the interaction between retina-specific transcription factors and cis-regulatory elements in the mammalian retina. In this proposed study, we will use a combination of molecular, biochemical, and genomics analyses to dissect the functionality of DNA methylation on transcriptional regulation throughout the genome of the developing and diseased human retina. In Aim 1, we will employ quantitative gene-specific analysis of epigenetically modified DNA to test the hypothesis that photoreceptor-specific regulatory elements are actively demethylated during human retinal development. In Aim 2, we will biochemically characterize purified human CRX-DNA binding motif complexes to test the hypothesis that epigenetically modified DNAs dampen CRX's binding affinity. In Aim 3, we will employ genomics and bioinformatics methodologies to characterize global epigenetic regulation in the clinical context of age-related macular degeneration (AMD). The results of these proposed studies will not only fill a void in our understanding of photoreceptor development, but will also identify novel aspects of epigenetic gene regulatory mechanisms in the retina. !


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$2,325 )
2023	2018	JAMES MADISON UNIVERSITY	800 S MAIN ST	HARRISONBURG	VA	22801	HARRISONBURG CITY	USA	Vision Research	000	1	12/1/2022	NEW	-$2,325
														Subtotal = -$2,325

Issue Date FY: 2018 ( Subtotal = $463,915 )
2018	2018	JAMES MADISON UNIVERSITY	MSC 5719	HARRISONBURG	VA	22807	HARRISONBURG CITY	USA	Vision Research	000	1	8/23/2018	NEW	$463,915
														Subtotal = $463,915

Grand Total All Awards = $461,590

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Dissecting the biochemical role of epigenetically modified regulatory sequences within the genomes of retinal neurons (A1)

Award Number: R15EY028725

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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