title: ICR noncoding RNA expression controls imprinting and DNA replication at the Dlk1-Dio3 domain.
abstract: Imprinted genes play essential roles in development, and their allelic expression is mediated by imprinting control regions (ICRs). The Dlk1-Dio3 locus is among the few imprinted domains controlled by a paternally methylated ICR. The unmethylated maternal copy activates imprinted expression early in development through an unknown mechanism. We find that in mouse embryonic stem cells (ESCs) and in blastocysts, this function is linked to maternal, bidirectional expression of noncoding RNAs (ncRNAs) from the ICR. Disruption of ICR ncRNA expression in ESCs affected gene expression in cis, led to acquisition of aberrant histone and DNA methylation, delayed replication timing along the domain on the maternal chromosome, and changed its subnuclear localization. The epigenetic alterations persisted during differentiation and affected the neurogenic potential of the stem cells. Our data indicate that monoallelic expression at an ICR of enhancer RNA-like ncRNAs controls imprinted gene expression, epigenetic maintenance processes, and DNA replication in embryonic cells.
authors.affiliation: Institute of Molecular Genetics (IGMM), CNRS UMR5535 and University of Montpellier, 1919 Route de Mende, Montpellier 34293, France.
authors.forename: Satya K
authors.initials: SK
authors.lastname: Kota
authors.affiliation: Institute of Molecular Genetics (IGMM), CNRS UMR5535 and University of Montpellier, 1919 Route de Mende, Montpellier 34293, France.
authors.forename: David
authors.initials: D
authors.lastname: Llères
authors.affiliation: Institute of Functional Genomics (IGF), CNRS and University of Montpellier, 141 rue de la Cardonille, Montpellier 34090, France.
authors.forename: Tristan
authors.initials: T
authors.lastname: Bouschet
authors.affiliation: Institute of Molecular Genetics (IGMM), CNRS UMR5535 and University of Montpellier, 1919 Route de Mende, Montpellier 34293, France.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Hirasawa
authors.affiliation: Institute of Molecular Genetics (IGMM), CNRS UMR5535 and University of Montpellier, 1919 Route de Mende, Montpellier 34293, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Marchand
authors.affiliation: Institute of Molecular Genetics (IGMM), CNRS UMR5535 and University of Montpellier, 1919 Route de Mende, Montpellier 34293, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Begon-Pescia
authors.affiliation: Institute of Molecular Genetics (IGMM), CNRS UMR5535 and University of Montpellier, 1919 Route de Mende, Montpellier 34293, France.
authors.forename: Ildem
authors.initials: I
authors.lastname: Sanli
authors.affiliation: Institute of Molecular Genetics (IGMM), CNRS UMR5535 and University of Montpellier, 1919 Route de Mende, Montpellier 34293, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Arnaud
authors.affiliation: Institute of Functional Genomics (IGF), CNRS and University of Montpellier, 141 rue de la Cardonille, Montpellier 34090, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Journot
authors.affiliation: Institute of Molecular Genetics (IGMM), CNRS UMR5535 and University of Montpellier, 1919 Route de Mende, Montpellier 34293, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Girardot
authors.affiliation: Institute of Molecular Genetics (IGMM), CNRS UMR5535 and University of Montpellier, 1919 Route de Mende, Montpellier 34293, France. Electronic address: robert.feil@igmm.cnrs.fr.
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D019175:DNA Methylation; D004261:DNA Replication; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D044127:Epigenesis, Genetic; D018392:Genomic Imprinting; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007453:Iodide Peroxidase / Q000235:genetics*; D019901:Locus Control Region; D051379:Mice; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D022661:RNA, Untranslated; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase