Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 22, Issue 5, Pages 370-U111Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3005
Keywords
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Funding
- Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research
- French Fondation de la Recherche Medical starting grant [AJE201132]
- Fondation ARC pour la Recherche sur le Cancer under the program ATIP-AVENIR
- European EpiGeneSys network of excellence
- Chilean Millennium Science Initiative grant [P10/063-F]
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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.
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