It’s always nice to have options, but nowadays there are often so many choices that you can drive yourself crazy making a decision, just ask LeBron James. A recent Nature paper shows that even genes need a little input from DNA methylation when they consider using alternative gene promoters. Joseph Costello at UCSF and colleagues indicate that intragenic DNA methylation can help genes choose or refuse a transcription start site (TSS) that may be outside the norm.
From high-resolution DNA methylation mapping of 24.7 million CpG sites in human brain, the researchers found that
- 34% of all intragenic CpG islands were methylated, compared with only 3% of CpG islands in 5’ promoters
- Tissue-specific methylation was more common in intragenic CpG islands than in 5’ promoters
- Intragenic CpG islands overlapped with markers of transcription initiation, and unmethylated CpG islands overlapped with trimethylated H3K4 (a histone mark enriched at promoters)
- Tissue-specific methylation of the human SHANK3 locus and of its mouse homolog regulated intragenic promoter activity
” Recent work from Zilberman (Science) and Jacobsen (PNAS) has show gene body methylation is ancient in evolutionary terms, suggesting an important, conserved but undisclosed function. Our study picks up from there, shows conservation of gene body methylation (limited to two species) is tissue and cell type specific. Further, we identify a major function, regulation of alternative promoters embedded in gene body. The question that remains is what is being made from alternative promoters…non-coding RNA, protein isoforms? Probably some of both,” shared Costello.
These findings suggest that DNA methylation may play an even bigger role in regulating alternative intragenic promoters than in controlling conventional 5’ promoters. There’s no alternative to getting full report at Nature, July 2010.