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.
Highlights
While intron retention (IR) is considered a widely conserved and distinct mechanism of gene expression control, its regulation is poorly understood
We show that lower levels of DNA methylation near 50 and 30 splice junctions are significantly associated with increased IR in a myriad of primary cells and cell lines
Since DNA methylation is known to regulate other forms of splicing, we explored its role in controlling IR
Summary
While intron retention (IR) is considered a widely conserved and distinct mechanism of gene expression control, its regulation is poorly understood. Altered DNA methylation levels and downstream binding of transcription factors as well as regulatory proteins such as CTCF and MeCP2 induce RNA Pol II stalling to promote alternative exon skipping and inclusion[12,13]. Lower DNA methylation levels near splice junctions have been associated with increased IR in normal human breast tissues[14] This latter finding raises the intriguing possibility that DNA methylation might regulate IR by altering RNA Pol II processivity and splice site recognition according to the ‘kinetic’ model. RNA Pol II stalling near splice junctions of retained introns could occur consequent to inefficient splicing factor recruitment[15,16] This ‘recruitment’ model of AS has been shown to function in the case of exon skipping, which is associated with DNA methylation changes[17,18]. Any functional connection between DNA methylation and the ‘kinetic’ and ‘recruitment’ models in the regulation of IR has been an open question to date
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