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Epigenetic and transcriptional mechanisms driving human pigmentation diversity

Award Number: R35GM151086
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Epigenetic and transcriptional mechanisms driving human pigmentation diversity - Melanin is the key determinant of human pigmentation that has evolved under natural selection and has led to diversification of human skin color. Importantly, the number of melanin-producing-melanocytes and their anatomical location do not vary among humans, only varying melanogenesis determines the human pigmentation diversity. Our long-term goal is to build a comprehensive understanding of the epigenetic and transcriptional machinery that dictate precise human melanogenesis gene expression programs that governs normal-range human pigmentation variation and disease susceptibility. The key insights about human melanogenesis have come from mapping genes involved in hypo- and hyper pigmentation diseases, Genome- wide Association Studies (GWAS) of normal-range skin and hair color variation in human populations and genetic studies on mouse coat color. Nonetheless, current genetic knowledge can explain only a fraction of skin color variation in humans suggesting that many loci controlling pigmentation remain unknown. By conducting a genome-wide CRISPR screen, PI has uncovered novel candidate genes driving human pigmentation. Among the novel pigmentation genes identified, we found that KLF transcription factors are differentially expressed in light and dark colored human melanocytes and play an antagonistic role in melanogenesis in a gene dosage dependent manner. We will investigate the cellular and molecular mechanisms of these closely related factors to understand their roles in human pigmentation variation. Consistent with other human phenotypes, we hypothesize that most DNA variants driving normal-range human pigmentation and skin disease susceptibility may lie in non-protein-coding regions of genome. We will map the cis-regulatory landscape of melanocytes from diverse color humans by performing unbiased epigenomic profiling to uncover putative enhancers with divergent gene regulatory activity. We will prioritize the candidate divergent enhancers for functional analysis by focusing on loci that have either previously been associated with skin color GWAS studies or overlap with novel melanogenesis genes identified by our genome-wide genetic screen. Through genetic perturbation studies we will confirm whether cis-regulatory changes affect gene expression quantitatively. Building on PI’s postdoctoral work, over the next five years, the lab will combine diverse approaches to understand the genotype-to-phenotype connection in human skin pigmentation variation. These approaches include pluripotent stem cell differentiation models that recapitulate human melanogenesis in vitro, genome-engineering, massively parallel reporter assays, single-cell profiling methods, quantitative melanin measurements, and validation experiments in transgenic mouse models. Through our studies on a highly quantifiable trait such as melanin, we will provide insights into how genotypic variation encoded in genome give rise to differences in gene expression and leads to phenotypic divergence within human species, which has implication for human development, health and disease.


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: 2025 ( Subtotal = $373,297 )
2025	2025	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	3	8/7/2025	NON-COMPETING CONTINUATION	$373,297
														Subtotal = $373,297

Issue Date FY: 2024 ( Subtotal = $623,114 )
2024	2024	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	1	5/30/2024	SUPPLEMENT FOR EXPANSION	$249,817
2024	2024	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	001	2	7/2/2024	NON-COMPETING CONTINUATION	$373,297
														Subtotal = $623,114

Issue Date FY: 2023 ( Subtotal = $373,297 )
2023	2023	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	1	8/22/2023	NEW	$373,297
														Subtotal = $373,297

Grand Total All Awards = $1,369,708

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Epigenetic and transcriptional mechanisms driving human pigmentation diversity

Award Number: R35GM151086

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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