Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment

Justin J. -L. Wong (), Dadi Gao, Trung V. Nguyen, Chau-To Kwok, Michelle van Geldermalsen, Rob Middleton, Natalia Pinello, Annora Thoeng, Rajini Nagarajah, Jeff Holst, William Ritchie () and John E. J. Rasko ()
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Justin J. -L. Wong: Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney
Dadi Gao: Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney
Trung V. Nguyen: Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney
Chau-To Kwok: Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney
Michelle van Geldermalsen: Sydney Medical School, University of Sydney
Rob Middleton: Sydney Medical School, University of Sydney
Natalia Pinello: Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney
Annora Thoeng: Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney
Rajini Nagarajah: Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney
Jeff Holst: Sydney Medical School, University of Sydney
William Ritchie: Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney
John E. J. Rasko: Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract While intron retention (IR) is considered a widely conserved and distinct mechanism of gene expression control, its regulation is poorly understood. Here we show that DNA methylation directly regulates IR. We also find reduced occupancy of MeCP2 near the splice junctions of retained introns, mirroring the reduced DNA methylation at these sites. Accordingly, MeCP2 depletion in tissues and cells enhances IR. By analysing the MeCP2 interactome using mass spectrometry and RNA co-precipitation, we demonstrate that decreased MeCP2 binding near splice junctions facilitates IR via reduced recruitment of splicing factors, including Tra2b, and increased RNA polymerase II stalling. These results suggest an association between IR and a slower rate of transcription elongation, which reflects inefficient splicing factor recruitment. In summary, our results reinforce the interdependency between alternative splicing involving IR and epigenetic controls of gene expression.

Date: 2017
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DOI: 10.1038/ncomms15134

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