In a recent paper, researchers say that DNA methylation, nucleosomes, and the “GC architecture” of an exon and its flanking introns may actually act as a big “cut here” sign stuck to the DNA or RNA to show where splicing is supposed to happen.
Evidence that DNA methylation and nucleosomes are linked to splicing has been building, with various studies suggesting an association. But nucleosomes hang out in high-GC areas, and lots of GC also can mean lots of DNA methylation. And exons just normally have more GCs than introns do.
So, is splicing really regulated epigenetically or is this all a coincidence because exons just have more GC content?
To answer this questions, a group in Israel looked at two types of exons: a “differential GC” type, with exons that have more GC than neighboring introns, and a “leveled GC” type, with exons and introns that have the same GC content. They used the mCpG/CpG ratio to figure this out. Here’s what they found:
- DNA methylation was a big splicing sign for both types of exons.
- In differential GC exons, nucleosomes also contributed—there were more of them on differential exons compared with their flanking introns.
- In leveled GC exons, nucleosomes weren’t really players. Here, the exons have a much stronger DNA methylation signal vs. the introns. And intronic areas near the borders had even less methylation than elsewhere in the introns.
- Alternative exons had lower DNA methylation levels than constitutive exons.
“These results strongly support the hypothesis that DNA methylation communicates with the splicing machinery during the exon selection process,” says Gil Ast, lead author and chair of the Department of Human Molecular Genetics & Biochemistry at the Sackler Medical School, Tel Aviv University.
“Regarding the work, I hope that when studying chromatin structure and modifications, researchers will now regard and analyze the genome not as a whole, but as several different units based on their GC-architecture,” says Sahar Gelfman, also of the Sackler Medical School, Tel Aviv University. “That will provide stronger, clearer results as to the part these factors have in the processes that are taking place on both the DNA and RNA strands.”
See for yourself at Genome Research, March 2013.