title: H19 lncRNA controls gene expression of the Imprinted Gene Network by recruiting MBD1.
abstract: The H19 gene controls the expression of several genes within the Imprinted Gene Network (IGN), involved in growth control of the embryo. However, the underlying mechanisms of this control remain elusive. Here, we identified the methyl-CpG-binding domain protein 1 MBD1 as a physical and functional partner of the H19 long noncoding RNA (lncRNA). The H19 lncRNA-MBD1 complex is required for the control of five genes of the IGN. For three of these genes--Igf2 (insulin-like growth factor 2), Slc38a4 (solute carrier family 38 member 4), and Peg1 (paternally expressed gene 1)--both MBD1 and H3K9me3 binding were detected on their differentially methylated regions. The H19 lncRNA-MBD1 complex, through its interaction with histone lysine methyltransferases, therefore acts by bringing repressive histone marks on the differentially methylated regions of these three direct targets of the H19 gene. Our data suggest that, besides the differential DNA methylation found on the differentially methylated regions of imprinted genes, an additional fine tuning of the expressed allele is achieved by a modulation of the H3K9me3 marks, mediated by the association of the H19 lncRNA with chromatin-modifying complexes, such as MBD1. This results in a precise control of the level of expression of growth factors in the embryo.
authors.affiliation: Genetics and Development Department, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8104, University Paris Descartes, Institut Cochin, Paris 75014, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Monnier
authors.forename: Clémence
authors.initials: C
authors.lastname: Martinet
authors.forename: Julien
authors.initials: J
authors.lastname: Pontis
authors.forename: Irina
authors.initials: I
authors.lastname: Stancheva
authors.forename: Slimane
authors.initials: S
authors.lastname: Ait-Si-Ali
authors.forename: Luisa
authors.initials: L
authors.lastname: Dandolo
mesh_terms: D000483:Alleles; D000818:Animals; D019175:DNA Methylation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000502:physiology*; D018392:Genomic Imprinting / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D062085:RNA, Long Noncoding / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C094335:H19 long non-coding RNA; C489323:Mbd1 protein, mouse; D062085:RNA, Long Noncoding; D012261:Ribonucleoproteins
keywords: Cdkn1c; Dlk1; embryonic growth; genomic imprinting; long noncoding RNA partner