Demethylated HSATII DNA and HSATII RNA Foci Sequester PRC1 and MeCP2 into Cancer-Specific Nuclear Bodies

Abstract

SUMMARY This study reveals that high-copy satellite II (HSATII) sequences in the human genome can bind and impact distribution of chromatin regulatory proteins and that this goes awry in cancer. In many cancers, master regulatory proteins form two-types of cancer-specific nuclear bodies, caused by locus-specific deregulation of HSATII. 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 with reduced 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 act as molecular sponges and sequester chromatin regulatory proteins into abnormal nuclear bodies in cancer. The compartmentalization of regulatory proteins within nuclear structure, triggered by demethylation of “junk” repeats, raises the possibility that this contributes to further compromise of the epigenome and neoplastic progression.

Exosomes transmit retroelement RNAs to drive inflammation and immunosuppression in Ewing Sarcoma

“…These transcripts were present in both sense and antisense orientations (Extended Data Fig. 3a, b), in line with their bidirectional transcription under various stress conditions, during development, senescence and cancer [29][30][31][32] . Based on read counts, HSAT2 and HERV-K, but not ACRO1 (derived from the chr2p11.2, 4p11 and 21p11.2 regions), were significantly elevated in plasma EVs from patients with metastatic as compared to localized disease (Fig.…”

“…To characterize systemic inflammation in EwS pathogenesis, we analyzed 33 plasma specimens from 30 EwS patients, 17 of which were from the Technical University München (Germany; TUM cohort) and 13 from the Institut Curie (France; EW cohort). In most cases (23 of 33), blood was drawn at diagnosis prior to chemotherapy (see Extended Data Table 1).…”

DUX4-induced bidirectional HSATII satellite repeat transcripts form intranuclear double stranded RNA foci in human cell models of FSHD

“…In our model system, DUX4 induction of HSATII repeats was similarly associated with the formation of polycomb bodies and foci of DNA damage, as determined by immunodetection of the PRC1 complex protein BMI1 and foci of phospho-H2AX (Supplementary Material Figure S11A). The BMI1 foci did not co-localize with induced HSATII RNA foci (Supplementary Material Figure S11B), but did show strong co-localization with the phospho-H2AX foci suggesting that the PRC1 complex was accumulating at sites of DNA damage, although it is possible that they might also be associated with demethylated HSATII DNA regions in the genome as has been suggested (30).…”

“…DUX4-mediated induction of HSATII RNA might have other consequences as well. HSATII transcription has been associated with the formation of intranuclear foci of components of the PRC1 complex (polycomb bodies), which can potentially lead to de-repression of LINE-1 elements or other repeats (30). The DUX4-induced formation of polycomb bodies, as indicated by the BMI1 foci, are consistent with a model where HSATII transcription in DUX4 expressing cells might have a similar role in the formation of polycomb bodies and activation of LINE-1 repeats.…”

“…Locked nucleic acid, FITC conjugated HSATII probes were purchased from QIAGEN and are based on the sequence used in previous publications (30, 56, 57). Probe 1: 5’ FAM-ATTCCATTCAGATTCCATTCGATC detects the reverse HSATII transcript.…”