title: Sequence and epigenetic determinants in the regulation of the Math6 gene by Neurogenin3.
abstract: The bHLH factor Neurogenin3 initiates the differentiation program that leads to formation of pancreatic endocrine cells. Math6 is a closely related bHLH factor transiently activated downstream of Neurogenin3 in endocrine progenitors. Here we characterize the Math6 promoter and locate the Neurogenin3 binding site, thus confirming that Math6 is a genuine Neurogenin3 target. We also show that Math6 activation rates are largely controlled by epigenetic mechanisms involving the balance between activating H3K4 and repressive H3K27 methylation marks. High Math6 expression in the embryonic pancreas associates with an H3K4me3-only state, whereas low Math6 expression in differentiated endocrine cells correlates with chromatin dually marked with H3K4me3/H3K27me3, a feature originally associated with developmental genes that are repressed but poised for activation in ES cells. Importantly, we show that Neurogenin3 can trigger the conversion of Math6 from a poorly transcribed bivalent to an active monovalent state in vitro, hence providing a mechanism whereby Neurogenin3 may activate Math6 in endocrine progenitors. Finally, because Neurogenin3-induced changes in histone methylation are observed at other endocrine gene promoters, we propose that this mechanism may contribute to the determination of endocrine cell fate by Neurogenin3 in the pancreas.
authors.affiliation: Diabetes and Obesity Laboratory, Institut D'Investigacions Biomèdiques August Pi i Sunyer-Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Pujadas
authors.forename: Francesc
authors.initials: F
authors.lastname: Felipe
authors.forename: Miriam
authors.initials: M
authors.lastname: Ejarque
authors.forename: Lidia
authors.initials: L
authors.lastname: Sanchez
authors.forename: Sara
authors.initials: S
authors.lastname: Cervantes
authors.forename: Francis C
authors.initials: FC
authors.lastname: Lynn
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
authors.forename: Rosa
authors.initials: R
authors.lastname: Gasa
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D001665:Binding Sites; D002454:Cell Differentiation; D055098:Endocrine Cells / Q000166:cytology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; D009419:Nerve Tissue Proteins; C449163:Atoh8 protein, mouse; C407737:Neurog3 protein, mouse; C523761:Kdm6b protein, mouse