Demethylated HSATII DNA and HSATII RNA Foci Sequester PRC1 and MeCP2 into Cancer-Specific Nuclear Bodies.
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 derepressed, 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.
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Lisa L
LL
Hall
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Meg
M
Byron
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Dawn M
DM
Carone
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Troy W
TW
Whitfield
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Gayle P
GP
Pouliot
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Andrew
A
Fischer
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Peter
P
Jones
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: jeanne.lawrence@umassmed.edu.
Jeanne B
JB
Lawrence
D019313:BRCA1 Protein / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D000073399:DNA Demethylation; D004276:DNA, Satellite / Q000235:genetics*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D066329:Protein Aggregates; D012313:RNA / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
C069077:BMI1 protein, human; D019313:BRCA1 Protein; D004276:DNA, Satellite; D051783:Methyl-CpG-Binding Protein 2; D063146:Polycomb-Group Proteins; D066329:Protein Aggregates; D012333:RNA, Messenger; D012313:RNA; D063150:Polycomb Repressive Complex 1
DNA methylation; breast cancer; cancer biomarkers; cancer epigenetics; centromere; nuclear structure; polycomb proteins; satellite heterochromatin