PcG proteins, DNA methylation, and gene repression by chromatin looping.

摘要: Many DNA hypermethylated and epigenetically silenced genes in adult cancers are Polycomb group (PcG) marked embryonic stem (ES) cells. We show that a large region upstream ( approximately 30 kb) of extending 60 kb around one such gene, GATA-4, is organized-in Tera-2 undifferentiated carcinoma (EC) cells-in topologically complex multi-loop conformation formed by multiple internal long-range contact regions near areas enriched for EZH2, other PcG proteins, the signature histone mark, H3K27me3. Small interfering RNA (siRNA)-mediated depletion EZH2 cells leads to significant reduction frequency associations at GATA-4 locus, seemingly dependent on affecting H3K27me3 enrichments those chromatin regions, accompanied modest increase transcription. The loops completely dissolve, loss proteins marks, when receive differentiation signals which induce 60-fold expression. In colon cancer cells, however, interactions increased setting where has no basal transcription encompass multiple, abnormally CpG islands, methyl-cytosine binding protein MBD2 localized these including ones gene promoter. Removing methylation through genetic disruption methyltransferases (DKO cells) occupancy decrease contacts, now more resemble Our findings reveal unexpected similarities higher order between stem/precursor cancers. also provide novel insight PcG-occupied H3K27me3-enriched can form physically interact cis single mammalian associate with poised, low state EC and, addition methylation, repressed