title: Epigenetic silencing of Oct4 by a complex containing SUV39H1 and Oct4 pseudogene lncRNA.
abstract: Pseudogene-derived, long non-coding RNAs (lncRNAs) act as epigenetic regulators of gene expression. Here we present a panel of new mouse Oct4 pseudogenes and demonstrate that the X-linked Oct4 pseudogene Oct4P4 critically impacts mouse embryonic stem cells (mESCs) self-renewal. Sense Oct4P4 transcription produces a spliced, nuclear-restricted lncRNA that is efficiently upregulated during mESC differentiation. Oct4P4 lncRNA forms a complex with the SUV39H1 HMTase to direct the imposition of H3K9me3 and HP1α to the promoter of the ancestral Oct4 gene, located on chromosome 17, leading to gene silencing and reduced mESC self-renewal. Targeting Oct4P4 expression in primary mouse embryonic fibroblasts causes the re-acquisition of self-renewing features of mESC. We demonstrate that Oct4P4 lncRNA plays an important role in inducing and maintaining silencing of the ancestral Oct4 gene in differentiating mESCs. Our data introduces a sense pseudogene-lncRNA-based mechanism of epigenetic gene regulation that controls the cross-talk between pseudogenes and their ancestral genes.
authors.affiliation: Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Scarola
authors.affiliation: Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Comisso
authors.affiliation: Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy.
authors.forename: Rhena
authors.initials: R
authors.lastname: Pascolo
authors.affiliation: Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Chiaradia
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro, 3, Madrid 28029, Spain.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Marion
authors.affiliation: 1] Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy [2] Department of Medical and Biological Sciences, University of Udine; Piazzale Massimiliano Kolbe 1, Udine 33100, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro, 3, Madrid 28029, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
authors.affiliation: 1] Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy [2] Department for Life Sciences, University of Trieste, Via Weiss 2, Trieste 34128, Italy.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schoeftner
authors.affiliation: 1] Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, Trieste 34149, Italy [2] Department of Medical and Biological Sciences, University of Udine; Piazzale Massimiliano Kolbe 1, Udine 33100, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Benetti
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism; D047468:Immunoprecipitation; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D041681:NIH 3T3 Cells; D050814:Octamer Transcription Factor-3 / Q000235:genetics*; D011544:Pseudogenes / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases