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DNA methylation (meDNA) is a suspected modulator of alternative splicing,while splicing in turn is involved in tumour formations nearly as frequently asDNA mutations. Yet, the impact of meDNA on tumorigenesis via its effect onsplicing has not been thoroughly explored. Here, we find that HCT116 coloncarcinoma cells inactivated for the DNA methylases DNMT1 and DNMT3b undergo apartial epithelial to mesenchymal transition (EMT) associated with alternativesplicing of the CD44 transmembrane receptor. The skipping of CD44 variant exonsis in part explained by altered expression or splicing of splicing andchromatin factors. A direct effect of meDNA on alternative splicing wassustained by transient depletion of DNMT1 and the methyl-binding genes MBD1,MBD2, and MBD3. Yet, local changes in intragenic meDNA also altered recruitmentof MBD1 protein and of the chromatin factor HP1$\gamma$ known to altertranscriptional pausing and alternative splicing decisions. We further testedif meDNA level has sufficiently strong direct impact on the outcome ofalternative splicing to have a predictive value in the MCF10A model for breastcancer progression and in patients with acute lymphoblastic leukemia (B ALL).We found that a small number of differentially spliced genes mostly involved insplicing and signal transduction is systematically correlated with local meDNA.Altogether, our observations suggest that, although DNA methylation hasmultiple avenues to alternative splicing, its indirect effect may be alsomediated through alternative splicing isoforms of these sensors of meDNA.

CD44 alternative splicing is a sensor of intragenic DNA methylation in tumors