title: Genetic and epigenetic determinants of neurogenesis and myogenesis.
abstract: The regulatory networks of differentiation programs have been partly characterized; however, the molecular mechanisms of lineage-specific gene regulation by highly similar transcription factors remain largely unknown. Here we compare the genome-wide binding and transcription profiles of NEUROD2-mediated neurogenesis with MYOD-mediated myogenesis. We demonstrate that NEUROD2 and MYOD bind a shared CAGCTG E box motif and E box motifs specific for each factor: CAGGTG for MYOD and CAGATG for NEUROD2. Binding at factor-specific motifs is associated with gene transcription, whereas binding at shared sites is associated with regional epigenetic modifications but is not as strongly associated with gene transcription. Binding is largely constrained to E boxes preset in an accessible chromatin context that determines the set of target genes activated in each cell type. These findings demonstrate that the differentiation program is genetically determined by E box sequence, whereas cell lineage epigenetically determines the availability of E boxes for each differentiation program.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Abraham P
authors.initials: AP
authors.lastname: Fong
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Yao
authors.forename: Jun Wen
authors.initials: JW
authors.lastname: Zhong
authors.forename: Yi
authors.initials: Y
authors.lastname: Cao
authors.forename: Walter L
authors.initials: WL
authors.lastname: Ruzzo
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gentleman
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
mesh_terms: D000107:Acetylation; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D024721:E-Box Elements; D024202:Electrophoretic Mobility Shift Assay; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D057890:Epigenomics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D051379:Mice; D024510:Muscle Development / Q000502:physiology*; D017570:MyoD Protein / Q000235:genetics* / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015534:Trans-Activators; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D002843:Chromatin; D006657:Histones; D017570:MyoD Protein; D009479:Neuropeptides; D015534:Trans-Activators; C057363:MyoD1 myogenic differentiation protein; C098995:Neurod2 protein, mouse