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Epigenetic and transcriptional mechanisms driving human pigmentation diversity

驱动人类色素沉着多样性的表观遗传和转录机制

基本信息

批准号：
10715498
负责人：
Vivek Kumar Bajpai
金额：
$ 37.33万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10715498
关键词：
Affect Anatomy Automobile Driving Biological Assay CRISPR screen Candidate Disease Gene Cells Chromosome Mapping Code Color Control Locus DNA Darkness Disease Disease susceptibility Enhancers Epigenetic Process Evolution Gene Dosage Gene Expression Genes Genetic Genetic Screening Genetic Transcription Genetic study Genome Genome engineering Genotype Goals Hair Color Health Human Human Development In Vitro Instruction Knowledge Light Location Maps Measurement Melanins Melanogenesis Methods Modeling Molecular Mus Natural Selections Normal Range Phenotype Pigmentation physiologic function Pigments Play Pluripotent Stem Cells Postdoctoral Fellow Production Regulator Genes Reporter Role Skin Pigmentation Transgenic Mice Validation Variant Work differential expression epigenomic profiling experimental study genome wide association study genome-wide human population study insight melanocyte mouse model novel programs skin color skin disorder stem cell differentiation trait transcription factor

项目摘要

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.

黑色素是人类色素沉着的关键决定因素，在自然选择下进化并导致