Journal
JOURNAL OF CELL BIOLOGY
Volume 219, Issue 11, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201910149
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Funding
- National Institutes of Health [HD093383]
- National Science Foundation Center for Cell Manufacturing (CMaT) [164805]
- Regenerative Engineering and Medicine Center at the University of Georgia
- Georgia Cancer Coalition
- U.S. Department of AgricultureNational Institute of Food and Agriculture-National Institutes of Health dual-purpose grant [2020-67015-30882]
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The polycomb group protein CBX2 is an important epigenetic reader involved in cell proliferation and differentiation. While CBX2 overexpression occurs in a wide range of human tumors, targeted deletion results in homeotic transformation, proliferative defects, and premature senescence. However, its cellular function(s) and whether it plays a role in maintenance of genome stability remain to be determined. Here, we demonstrate that loss of CBX2 in mouse fibroblasts induces abnormal large-scale chromatin structure and chromosome instability. Integrative transcriptome analysis and ATAC-seq revealed a significant dysregulation of transcripts involved in DNA repair, chromocenter formation, and tumorigenesis in addition to changes in chromatin accessibility of genes involved in lateral sclerosis, basal transcription factors, and folate metabolism. Notably, Cbx2(-)(/-) cells exhibit prominent decondensation of satellite DNA sequences at metaphase and increased sister chromatid recombination events leading to rampant chromosome instability. The presence of extensive centromere and telomere defects suggests a prominent role for CBX2 in heterochromatin homeostasis and the regulation of nuclear architecture.
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