Tuesday, October 4, 2011

whoa! DNA methylation regulates alternative splicing!

What regulates alternative splicing of pre-mRNA has always been an enigma -- it is especially important in cancer research where it seems many genes become alternatively spliced, potentially giving them novel functions, or making them inactive.  In a Nature epub by Shukla et al., we see that DNA methylation may be involved in this process; the authors show that CTCF binding permitted inclusion of upstream exons by causing a pause in RNA pol II and thus slowing the transcription rate.  Furthermore, they demonstrated that (as we already know) CTCF binding to its target sequence can be prevented by DNA methylation. When this occurred, the upstream exon was excluded from the maturely spliced mRNA transcript.  These findings were shown in a model system, but also occurred as a global phenomenon.  It follows that loss of intergenic or intronic DNA methylation, as occurs frequently in cancer, not only causes genomic instability and potentially activates previously silenced genes, but now may result in the mRNA scramble that we see as well.  Presumably alternative variants that provide a growth advantage for the cell will be selected for -- meanwhile for those of us studying regulation of altered methylation patterns, we just got more places to all about it at Nature --CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing by Shukla et al.

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