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Nat Struct Mol Biol. 2015 May;22(5):370-6. doi: 10.1038/nsmb.3005. Epub 2015 Apr 6.

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

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ATIP-AVENIR team, Institute of Human Genetics, CNRS UPR 1142, Montpellier, France.
Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.


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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