Model of the Relationship between Promoter-Proximal DNA Methylation and Transcriptional Efficiency

<p>Four alternative DNA methylation states are shown, along with the acetylation (K9ac) and methylation (K9me) states of H3K9. In the presence of “distal” DNA methylation (>1–2 kb from the TSS), transcription may not be effected. This would allow for methylation and silencing of intronic parasitic elements, such as SINE and LINES or “cryptic promoters”, while allowing for efficient transcription of bona fide genes. Dense DNA methylation on the order of 1 kb from the TSS may have a modest effect on elongation efficiency, perhaps by altering the chromatin structure of the promoter proximal region, as we have shown previously [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030027#pgen-0030027-b019" target="_blank">19</a>]. Promoter proximal methylation (∼300 bp from the TSS) may have a dramatic effect on transcription initiation, as a result of altering promoter chromatin structure, as described here. Methylation of the promoter region itself leads to robust silencing of the gene, as is frequently observed for CpG island promoters in cancer cells.