Demethylated HSATII DNA and aberrant HSATII RNA foci act as sponges for epigenetic factors in cancer

This study reveals that the millions of satellite II (HSATII) sequences in the human genome can bind and impact distribution of epigenetic regulators, and that this goes awry in cancer. In many cancers master epigenetic factors form two-types of cancer-specific nuclear bodies, caused by locus-specific deregulation of HSATII DNA and RNA, respectively. DNA demethylation at the 1q12 mega-satellite, common in cancer, causes PRC1 aggregation into prominent Cancer-Associated Polycomb (CAP) bodies. These loci remain silent, whereas HSATII loci in regions low in PRC1 become de-repressed, reflecting imbalanced distribution of UbH2A on these and other PcG-regulated loci. Large nuclear foci of HSATII RNA form and sequester copious MeCP2 into Cancer-Associated Satellite Transcript (CAST) bodies. Hence, HSATII DNA and RNA have an exceptional capacity to “sponge” epigenetic factors into abnormal nuclear bodies in cancer. Results support a new concept that demethylation of “junk” repeats can trigger further epigenetic compromise by compartmentalizing regulatory factors within nuclear structure. Examination of the distribution of ubiquityl Histone H2A in U2OS and Tig-1 fibroblast cells. Input samples are included as controls.