title: CtBP and associated LSD1 are required for transcriptional activation by NeuroD1 in gastrointestinal endocrine cells.
abstract: Gene expression programs required for differentiation depend on both DNA-bound transcription factors and surrounding histone modifications. Expression of the basic helix-loop-helix (bHLH) protein NeuroD1 is restricted to endocrine cells in the gastrointestinal (GI) tract, where it is important for endocrine differentiation. RREB1 (RAS-responsive element binding protein 1), identified as a component of the CtBP corepressor complex, binds to nearby DNA elements to associate with NeuroD and potentiate transcription of a NeuroD1 target gene. Transcriptional activation by RREB1 depends on recruitment of CtBP with its associated proteins, including LSD1, through its PXDLS motifs. The mechanism of transcriptional activation by CtBP has not been previously characterized. Here we found that activation was dependent on the histone H3 lysine 9 (H3K9) demethylase activity of LSD1, which removes repressive methyl marks from dimethylated H3K9 (H3K9Me2), to facilitate subsequent H3K9 acetylation by the NeuroD1-associated histone acetyltransferase, P300/CBP-associated factor (PCAF). The secretin, β-glucokinase, insulin I, and insulin II genes, four known direct targets of NeuroD1 in intestinal and pancreatic endocrine cells, all show similar promoter occupancy by CtBP-associated proteins and PCAF, with acetylation of H3K9. This work may indicate a mechanism for selective regulation of transcription by CtBP and LSD1 involving their association with specific transcription factors and cofactors to drive tissue-specific transcription.
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Subir K
authors.initials: SK
authors.lastname: Ray
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: H Joyce
authors.initials: HJ
authors.lastname: Li
authors.affiliation: Center for Clinical Research, University of Freiburg Medical Center, Freiburg, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Metzger
authors.affiliation: Center for Clinical Research, University of Freiburg Medical Center, Freiburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Department of Medicine, Division of Gastroenterology, University of Massachusetts Medical School, Worcester, Massachusetts, USA andrew.leiter@umassmed.edu.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Leiter
mesh_terms: D000107:Acetylation; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019858:Enteroendocrine Cells / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012633:Secretin / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics*; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000429:Alcohol Oxidoreductases; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D056466:Histone Demethylases; D006657:Histones; D008239:Lysine; D009419:Nerve Tissue Proteins; D012633:Secretin; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C101743:RREB1 protein, human; C093564:Neurogenic differentiation factor 1; C096794:C-terminal binding protein; C495195:KDM1A protein, human
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