Hot spots of DNA double-strand breaks and genomic contacts of human rDNA units are involved in epigenetic regulation

Abstract

DNA double-strand breaks (DSBs) are involved in many cellular mechanisms, including replication, transcription, and genome rearrangements. The recent observation that hot spots of DSBs in human chromosomes delimit DNA domains that possess coordinately expressed genes suggests a strong relationship between the organization of transcription patterns and hot spots of DSBs. In this study, we performed mapping of hot spots of DSBs in a human 43-kb ribosomal DNA (rDNA) repeated unit. We observed that rDNA units corresponded to the most fragile sites in human chromosomes and that these units possessed at least nine specific regions containing clusters of extremely frequently occurring DSBs, which were located exclusively in non-coding intergenic spacer (IGS) regions. The hot spots of DSBs corresponded to only a specific subset of DNase-hypersensitive sites, and coincided with CTCF, PARP1, and HNRNPA2B1 binding sites, and H3K4me3 marks. Our rDNA-4C data indicate that the regions of IGS containing the hot spots of DSBs often form contacts with specific regions in different chromosomes, including the pericentromeric regions, as well as regions that are characterized by H3K27ac and H3K4me3 marks, CTCF binding sites, ChIA-PET and RIP signals, and high levels of DSBs. The data suggest a strong link between chromosome breakage and several different mechanisms of epigenetic regulation of gene expression.

Brachypodium distachyon – A Useful Model in the Qualification of Mutagen-Induced Micronuclei Using Multicolor FISH

“…Moreover, an additional locus of 35S rDNA was present after MH treatment in barley cells, which suggests that either a duplication or double strand breaks (DBS) occurred within the 35S rDNA locus. Though the NOR regions were found to exhibit increased fragility both in some plants [44, 45] and in humans [46], we did not observe this in Brachypodium cells. A different sensitivity of 5S rDNA and 25S rDNA sequences was also reported in C .…”

Predicting double-strand DNA breaks using epigenome marks or DNA at kilobase resolution

“…Based on lasso regression, we found that the CTCF motif had the highest beta coefficient (β = 3.22), corresponding to OR = 25 (Fig. 7c), supporting recent evidence showing that long-range contacts are involved in DNA repair [25,35,41]. Furthermore, motifs of tumor proteins p53, p63, and p73 had high coefficients (β > 2.03, OR > 7.6), in agreement with previous predictions based on To assess the significance of those motifs, we built a logistic regression model without any regularization including all motifs with β > 0.5.…”

Epigenetic maintenance of topological domains in the highly rearranged gibbon genome

“…8; Smerdon 1991). In support of this model, open chromatin and the epigenetic marks found at TAD boundaries (e.g., H3K4me3 and CTCF) have been linked to chromatin fragility in human disease (De and Michor 2011;Tchurikov et al 2015), species evolution (Carbone et al 2009a;Lemaitre et al 2009), and simulation analyses (Berthelot et al 2015). Moreover, an in vitro study recently showed that chromosome loop anchors bound by CTCF and cohesin are vulnerable to DSBs mediated by topoisomerase 2B (TOP2B) and act as fragile sites for chromosomal rearrangements (Canela et al 2017).…”