title: 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.
authors.affiliation: Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia tchurikov@eimb.ru.
authors.forename: Nickolai A
authors.initials: NA
authors.lastname: Tchurikov
authors.affiliation: Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia.
authors.forename: Daria M
authors.initials: DM
authors.lastname: Fedoseeva
authors.affiliation: Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Sosin
authors.affiliation: Group of Postgenomic Studies, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia.
authors.forename: Anastasia V
authors.initials: AV
authors.lastname: Snezhkina
authors.affiliation: Group of Postgenomic Studies, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia.
authors.forename: Nataliya V
authors.initials: NV
authors.lastname: Melnikova
authors.affiliation: Group of Postgenomic Studies, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Kudryavtseva
authors.affiliation: Laboratory of DNA-Protein Interactions, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia.
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Kravatsky
authors.affiliation: Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Kretova
mesh_terms: D000076246:CCCTC-Binding Factor; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D002877:Chromosomes, Human / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D019175:DNA Methylation / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics*; D003850:Deoxyribonuclease I / Q000378:metabolism; D044127:Epigenesis, Genetic; D015894:Genome, Human; D057809:HEK293 Cells; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D004275:DNA, Ribosomal; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D006657:Histones; D012097:Repressor Proteins; D011065:Poly(ADP-ribose) Polymerases; D003850:Deoxyribonuclease I; D008239:Lysine
keywords: 4C; HNRNPA2B1; IGS; PARP1; double-strand breaks; fragile sites; rDNA