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.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing / genetics*
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Argonaute Proteins / genetics
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Cell Cycle Proteins / genetics
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Cell Line
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Chromatin / genetics*
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DEAD-box RNA Helicases / genetics
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Enhancer of Zeste Homolog 2 Protein
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Epithelial Cells
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Eukaryotic Initiation Factors / genetics
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F-Box Proteins / metabolism
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Histones / metabolism
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Humans
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Jumonji Domain-Containing Histone Demethylases / metabolism
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MCF-7 Cells
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Neoplasm Proteins
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Polycomb Repressive Complex 2 / genetics
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Polycomb Repressive Complex 2 / metabolism
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Polycomb-Group Proteins / metabolism
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Polypyrimidine Tract-Binding Protein / genetics
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RNA Interference
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RNA Precursors / genetics*
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RNA, Long Noncoding / genetics*
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RNA, Small Interfering
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Receptor, Fibroblast Growth Factor, Type 2 / genetics*
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Ribonuclease III / genetics
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Transcription Factors
Substances
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AGO1 protein, human
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AGO2 protein, human
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Argonaute Proteins
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Cell Cycle Proteins
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Chromatin
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Eukaryotic Initiation Factors
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F-Box Proteins
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Histones
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Neoplasm Proteins
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Polycomb-Group Proteins
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RNA Precursors
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RNA, Long Noncoding
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RNA, Small Interfering
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SUZ12 protein, human
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Transcription Factors
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Polypyrimidine Tract-Binding Protein
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Jumonji Domain-Containing Histone Demethylases
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KDM2A protein, human
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EZH1 protein, human
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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Polycomb Repressive Complex 2
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FGFR2 protein, human
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Receptor, Fibroblast Growth Factor, Type 2
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DICER1 protein, human
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Ribonuclease III
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DEAD-box RNA Helicases