A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature

• Published in: Nature structural & molecular biology Vol. 22; no. 5; pp. 370 - 376
• Main Authors: Gonzalez, Inma, Munita, Roberto, Agirre, Eneritz, Dittmer, Travis A, Gysling, Katia, Misteli, Tom, Luco, Reini F
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2015; Nature Publishing Group
• Subjects: 13; 13/89; 38; 38/109; 38/77; 38/90; 631/337/100/2285; 631/337/1645/1946; 631/337/384/2568; 82; Alternative Splicing - genetics; Antisense RNA; Argonaute Proteins - genetics; Biochemistry; Biological Microscopy; Cell Cycle Proteins - genetics; Cell Line; Chromatin; Chromatin - genetics; DEAD-box RNA Helicases - genetics; Enhancer of Zeste Homolog 2 Protein; Epithelial Cells; Eukaryotic Initiation Factors - genetics; F-Box Proteins - metabolism; Genetics; Histones - metabolism; Humans; Jumonji Domain-Containing Histone Demethylases - metabolism; Life Sciences; MCF-7 Cells; Membrane Biology; Neoplasm Proteins; Physiological aspects; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Polycomb-Group Proteins - metabolism; Polypyrimidine Tract-Binding Protein - genetics; Protein Structure; Receptor, Fibroblast Growth Factor, Type 2 - genetics; Ribonuclease III - genetics; RNA Interference; RNA Precursors - genetics; RNA splicing; RNA, Long Noncoding - genetics; RNA, Small Interfering; Structure; Transcription Factors; United States
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.3005

The evolutionarily conserved antisense long noncoding RNA asFGFR2 influences cell type–specific alternative-splicing patterns of FGFR2 by recruiting chromatin modifiers to the locus. 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.