title: Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2.
abstract: Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-β (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages. We show that the splicing regulator Polypyrimidine tract-binding protein 1 (PTBP1) promotes the retention of an intron in the 5'-UTR of Yy2 mRNA that confers sensitivity to 4E-BP-mediated translational suppression. Thus, we conclude that YY2 is a major regulator of mESC self-renewal and lineage commitment and document a multilayer regulatory mechanism that controls its expression.
authors: Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
authors: Soroush
authors: S
authors: Tahmasebi
authors: Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
authors: Seyed Mehdi
authors: SM
authors: Jafarnejad
authors: Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
authors: Ingrid S
authors: IS
authors: Tam
authors: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors: Thomas
authors: T
authors: Gonatopoulos-Pournatzis
authors: Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
authors: Edna
authors: E
authors: Matta-Camacho
authors: Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
authors: Yoshinori
authors: Y
authors: Tsukumo
authors: Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
authors: Akiko
authors: A
authors: Yanagiya
authors: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 07103.
authors: Wencheng
authors: W
authors: Li
authors: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, 6525GA, The Netherlands.
authors: Yaser
authors: Y
authors: Atlasi
authors: Department of Human Genetics, McGill University, Montreal, QC H3A 1A3, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada.
authors: Maxime
authors: M
authors: Caron
authors: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors: Ulrich
authors: U
authors: Braunschweig
authors: Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
authors: Dana
authors: D
authors: Pearl
authors: Department of Anesthesia, McGill University, Montreal, QC, H3G 1Y6, Canada.
authors: Arkady
authors: A
authors: Khoutorsky
authors: Patrick Wild Centre, Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, United Kingdom.
authors: Christos G
authors: CG
authors: Gkogkas
authors: Department of Human Genetics, McGill University, Montreal, QC H3A 1A3, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada.
authors: Robert
authors: R
authors: Nadon
authors: Department of Human Genetics, McGill University, Montreal, QC H3A 1A3, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada.
authors: Guillaume
authors: G
authors: Bourque
authors: Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Medicine, McGill University Health Center, Montreal, QC H3A 1A3, Canada.
authors: Xiang-Jiao
authors: XJ
authors: Yang
authors: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 07103.
authors: Bin
authors: B
authors: Tian
authors: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, 6525GA, The Netherlands.
authors: Hendrik G
authors: HG
authors: Stunnenberg
authors: Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Human Genetics, McGill University, Montreal, QC H3A 1A3, Canada.
authors: Yojiro
authors: Y
authors: Yamanaka
authors: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Benjamin J
authors: BJ
authors: Blencowe
authors: Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Medicine, McGill University Health Center, Montreal, QC H3A 1A3, Canada.
authors: Vincent
authors: V
authors: Giguère
authors: Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; nahum.sonenberg@mcgill.ca.|Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors: Nahum
authors: N
authors: Sonenberg
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D000066673:Cell Self Renewal / Q000235:genetics / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics; D007438:Introns; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010750:Phosphoproteins; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C098925:Esrrb protein, mouse; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D050814:Octamer Transcription Factor-3; D010750:Phosphoproteins; C494174:Pou5f1 protein, mouse; C573992:Ptbp1 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C509847:YY2 protein, mouse; C494699:Yy1 protein, mouse; D038941:Polypyrimidine Tract-Binding Protein
keywords: 4E-BPs; PTBP; YY2; embryonic stem cell; mRNA translation