title: Human genetic variation within neural crest enhancers: molecular and phenotypic implications.
abstract: Developmental gene expression programmes are coordinated by the specialized distal cis-regulatory elements called enhancers, which integrate lineage- and signalling-dependent inputs to guide morphogenesis. In previous work, we characterized the genome-wide repertoire of active enhancers in human neural crest cells (hNCC), an embryonic cell population with critical roles in craniofacial development. We showed that in hNCC, co-occupancy of a master regulator TFAP2A with nuclear receptors NR2F1 and NR2F2 correlates with the presence of permissive enhancer chromatin states. Here, we take advantage of pre-existing human genetic variation to further explore potential cooperation between TFAP2A and NR2F1/F2. We demonstrate that isolated single nucleotide polymorphisms affecting NR2F1/F2-binding sites within hNCC enhancers can alter TFAP2A occupancy and overall chromatin features at the same enhancer allele. We propose that a similar strategy can be used to elucidate other cooperative relationships between transcription factors involved in developmental transitions. Using the neural crest and its major contribution to human craniofacial phenotypes as a paradigm, we discuss how genetic variation might modulate the molecular properties and activity of enhancers, and ultimately impact human phenotypic diversity.
authors: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Alvaro
authors: A
authors: Rada-Iglesias
authors: Sara L
authors: SL
authors: Prescott
authors: Joanna
authors: J
authors: Wysocka
mesh_terms: D000483:Alleles; D000818:Animals; D051838:COUP Transcription Factor I / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D005145:Face / Q000033:anatomy & histology; D014644:Genetic Variation; D006801:Humans; D009024:Morphogenesis; D009432:Neural Crest / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051838:COUP Transcription Factor I; C497589:NR2F1 protein, human; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2
keywords: chromatin; cooperativity; craniofacial; enhancer; neural crest; single nucleotide polymorphism
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