title: A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature.
abstract: Alternative pre-mRNA splicing is a highly cell type-specific process essential to generating protein diversity. However, the mechanisms responsible for the establishment and maintenance of heritable cell-specific alternative-splicing programs are poorly understood. Recent observations point to a role of histone modifications in the regulation of alternative splicing. Here we report a new mechanism of chromatin-mediated splicing control involving a long noncoding RNA (lncRNA). We have identified an evolutionarily conserved nuclear antisense lncRNA, generated from within the human FGFR2 locus, that promotes epithelial-specific alternative splicing of FGFR2. The lncRNA acts through recruitment of Polycomb-group proteins and the histone demethylase KDM2a to create a chromatin environment that impairs binding of a repressive chromatin-splicing adaptor complex important for mesenchymal-specific splicing. Our results uncover a new function for lncRNAs in the establishment and maintenance of cell-specific alternative splicing via modulation of chromatin signatures.
authors: ATIP-AVENIR team, Institute of Human Genetics, CNRS UPR 1142, Montpellier, France.
authors: Inma
authors: I
authors: Gonzalez
authors: Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Roberto
authors: R
authors: Munita
authors: ATIP-AVENIR team, Institute of Human Genetics, CNRS UPR 1142, Montpellier, France.
authors: Eneritz
authors: E
authors: Agirre
authors: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Travis A
authors: TA
authors: Dittmer
authors: Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Katia
authors: K
authors: Gysling
authors: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Tom
authors: T
authors: Misteli
authors: ATIP-AVENIR team, Institute of Human Genetics, CNRS UPR 1142, Montpellier, France.
authors: Reini F
authors: RF
authors: Luco
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D060565:Argonaute Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D002843:Chromatin / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D004847:Epithelial Cells; D039642:Eukaryotic Initiation Factors / Q000235:genetics; D044783:F-Box Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D061986:MCF-7 Cells; D009363:Neoplasm Proteins; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics; D034622:RNA Interference; D012322:RNA Precursors / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D034741:RNA, Small Interfering; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics; D014157:Transcription Factors
chemical_list: C115848:AGO1 protein, human; C466422:AGO2 protein, human; D060565:Argonaute Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D039642:Eukaryotic Initiation Factors; D044783:F-Box Proteins; D006657:Histones; D009363:Neoplasm Proteins; D063146:Polycomb-Group Proteins; D012322:RNA Precursors; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; C430461:SUZ12 protein, human; D014157:Transcription Factors; D038941:Polypyrimidine Tract-Binding Protein; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; C103523:EZH1 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases