title: Genomic analysis reveals distinct mechanisms and functional classes of SOX10-regulated genes in melanocytes.
abstract: SOX10 is required for melanocyte development and maintenance, and has been linked to melanoma initiation and progression. However, the molecular mechanisms by which SOX10 guides the appropriate gene expression programs necessary to promote the melanocyte lineage are not fully understood. Here we employ genetic and epigenomic analysis approaches to uncover novel genomic targets and previously unappreciated molecular roles of SOX10 in melanocytes. Through global analysis of SOX10-binding sites and epigenetic characteristics of chromatin states, we uncover an extensive catalog of SOX10 targets genome-wide. Our findings reveal that SOX10 predominantly engages 'open' chromatin regions and binds to distal regulatory elements, including novel and previously known melanocyte enhancers. Integrated chromatin occupancy and transcriptome analysis suggest a role for SOX10 in both transcriptional activation and repression to regulate functionally distinct classes of genes. We demonstrate that distinct epigenetic signatures and cis-regulatory sequence motifs predicted to bind putative co-regulatory transcription factors define SOX10-activated and SOX10-repressed target genes. Collectively, these findings uncover a central role of SOX10 as a global regulator of gene expression in the melanocyte lineage by targeting diverse regulatory pathways.
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Temesgen D
authors.initials: TD
authors.lastname: Fufa
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Harris
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Watkins-Chow
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Levy
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: David U
authors.initials: DU
authors.lastname: Gorkin
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Derek E
authors.initials: DE
authors.lastname: Gildea
authors.affiliation: Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA, Department of Pediatrics, Division of Molecular Genetics, Duke University, Durham, NC 27708, USA and.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Song
authors.affiliation: Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA, Department of Pediatrics, Division of Molecular Genetics, Duke University, Durham, NC 27708, USA and.
authors.forename: Alexias
authors.initials: A
authors.lastname: Safi
authors.affiliation: Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA, Department of Pediatrics, Division of Molecular Genetics, Duke University, Durham, NC 27708, USA and.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Crawford
authors.affiliation: Molecular Cell Sciences Research Centre, St George's, University of London, London SW17 0RE, UK.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Sviderskaya
authors.affiliation: Molecular Cell Sciences Research Centre, St George's, University of London, London SW17 0RE, UK.
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Bennett
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Mccallion
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Stacie K
authors.initials: SK
authors.lastname: Loftus
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA, bpavan@mail.nih.gov.
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D057890:Epigenomics / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D055757:SOXE Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse