title: Snail regulates MyoD binding-site occupancy to direct enhancer switching and differentiation-specific transcription in myogenesis.
abstract: In skeletal myogenesis, the transcription factor MyoD activates distinct transcriptional programs in progenitors compared to terminally differentiated cells. Using ChIP-Seq and gene expression analyses, we show that in primary myoblasts, Snail-HDAC1/2 repressive complex binds and excludes MyoD from its targets. Notably, Snail binds E box motifs that are G/C rich in their central dinucleotides, and such sites are almost exclusively associated with genes expressed during differentiation. By contrast, Snail does not bind the A/T-rich E boxes associated with MyoD targets in myoblasts. Thus, Snai1-HDAC1/2 prevent MyoD occupancy on differentiation-specific regulatory elements, and the change from Snail to MyoD binding often results in enhancer switching during differentiation. Furthermore, we show that a regulatory network involving myogenic regulatory factors (MRFs), Snai1/2, miR-30a, and miR-206 acts as a molecular switch that controls entry into myogenic differentiation. Together, these results reveal a regulatory paradigm that directs distinct gene expression programs in progenitors versus terminally differentiated cells.
authors: Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors: Vahab D
authors: VD
authors: Soleimani
authors: Hang
authors: H
authors: Yin
authors: Arezu
authors: A
authors: Jahani-Asl
authors: Hong
authors: H
authors: Ming
authors: Christel E M
authors: CE
authors: Kockx
authors: Wilfred F J
authors: WF
authors: van Ijcken
authors: Frank
authors: F
authors: Grosveld
authors: Michael A
authors: MA
authors: Rudnicki
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development / Q000235:genetics*; D017570:MyoD Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000502:physiology*; D061251:Primary Cell Culture; D011485:Protein Binding / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors