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

Tchurikov NA, Fedoseeva DM, Sosin DV, Snezhkina AV, Melnikova NV, Kudryavtseva AV, Kravatsky YV, Kretova OV - J Mol Cell Biol (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia tchurikov@eimb.ru.

No MeSH data available.


Related in: MedlinePlus

Comparison of CTCF binding and DNA methylation profiles with the observed pattern of hot spots of DSBs inside rDNA. At the top, the position of nine hot spots of DSBs obtained from Illumina reads is presented. Thin red lines show the position of nine hot spots of DSBs inside the IGS. The raw data on CTCF binding and on DNA methylation in HEK293 cells were used for the mapping inside the rDNA unit (Accession numbers wgEncodeEH000396 and GSE27584, respectively). UCE/CP: upstream promoter element and core promoter.
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MJU038F2: Comparison of CTCF binding and DNA methylation profiles with the observed pattern of hot spots of DSBs inside rDNA. At the top, the position of nine hot spots of DSBs obtained from Illumina reads is presented. Thin red lines show the position of nine hot spots of DSBs inside the IGS. The raw data on CTCF binding and on DNA methylation in HEK293 cells were used for the mapping inside the rDNA unit (Accession numbers wgEncodeEH000396 and GSE27584, respectively). UCE/CP: upstream promoter element and core promoter.

Mentions: The data on the specific distribution of the hot spots of DSBs inside rDNA units prompted us to study the chromatin features in these regions. It is known that CTCF is associated with diverse regulatory events in the human genome. It can act as a transcriptional activator, repressor, and insulator, and can form chromatin loops (Holwerda and de Laat, 2013; Ong and Corces, 2014). The available raw data on CTCF binding sites in HEK293T cells were used for mapping inside rDNA. Figure 2 shows the profile of CTCF binding sites in rDNA. Most CTCF binding sites occurred inside the IGS. We observed that the major R4–R9 hot spots of DSBs coincided with the major peaks of CTCF binding sites. Moreover, there is a clear correlation between the frequencies of observed DSBs and the levels of CTCF binding inside the IGS. Nevertheless, there are CTCF binding sites in the regions where hot spots of DSBs were not detected, e.g. the regions around the coordinates 6500, 17000, and 42000 bp. The latter region corresponds to the upstream control element (UCE) and core promoter (CP) sequences (McStay and Grummt, 2008). The data indicate that, in rDNA units, CTCF recognizes not only the specific sites at DSBs, but some others as well. It might be that some peaks of CTCF binding originate from active rDNA units, while others originate from silenced units. The functional role of CTCF in different hot spots of DSBs is hard to predict. Nevertheless, the mapping data indicate a strong link between the regions that are important for regulation via CTCF and chromosome breakage at NORs. This analysis cannot discriminate the signals coming from active or inactive rDNA units.Figure 2


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

Tchurikov NA, Fedoseeva DM, Sosin DV, Snezhkina AV, Melnikova NV, Kudryavtseva AV, Kravatsky YV, Kretova OV - J Mol Cell Biol (2014)

Comparison of CTCF binding and DNA methylation profiles with the observed pattern of hot spots of DSBs inside rDNA. At the top, the position of nine hot spots of DSBs obtained from Illumina reads is presented. Thin red lines show the position of nine hot spots of DSBs inside the IGS. The raw data on CTCF binding and on DNA methylation in HEK293 cells were used for the mapping inside the rDNA unit (Accession numbers wgEncodeEH000396 and GSE27584, respectively). UCE/CP: upstream promoter element and core promoter.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4524424&req=5

MJU038F2: Comparison of CTCF binding and DNA methylation profiles with the observed pattern of hot spots of DSBs inside rDNA. At the top, the position of nine hot spots of DSBs obtained from Illumina reads is presented. Thin red lines show the position of nine hot spots of DSBs inside the IGS. The raw data on CTCF binding and on DNA methylation in HEK293 cells were used for the mapping inside the rDNA unit (Accession numbers wgEncodeEH000396 and GSE27584, respectively). UCE/CP: upstream promoter element and core promoter.
Mentions: The data on the specific distribution of the hot spots of DSBs inside rDNA units prompted us to study the chromatin features in these regions. It is known that CTCF is associated with diverse regulatory events in the human genome. It can act as a transcriptional activator, repressor, and insulator, and can form chromatin loops (Holwerda and de Laat, 2013; Ong and Corces, 2014). The available raw data on CTCF binding sites in HEK293T cells were used for mapping inside rDNA. Figure 2 shows the profile of CTCF binding sites in rDNA. Most CTCF binding sites occurred inside the IGS. We observed that the major R4–R9 hot spots of DSBs coincided with the major peaks of CTCF binding sites. Moreover, there is a clear correlation between the frequencies of observed DSBs and the levels of CTCF binding inside the IGS. Nevertheless, there are CTCF binding sites in the regions where hot spots of DSBs were not detected, e.g. the regions around the coordinates 6500, 17000, and 42000 bp. The latter region corresponds to the upstream control element (UCE) and core promoter (CP) sequences (McStay and Grummt, 2008). The data indicate that, in rDNA units, CTCF recognizes not only the specific sites at DSBs, but some others as well. It might be that some peaks of CTCF binding originate from active rDNA units, while others originate from silenced units. The functional role of CTCF in different hot spots of DSBs is hard to predict. Nevertheless, the mapping data indicate a strong link between the regions that are important for regulation via CTCF and chromosome breakage at NORs. This analysis cannot discriminate the signals coming from active or inactive rDNA units.Figure 2

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia tchurikov@eimb.ru.

No MeSH data available.


Related in: MedlinePlus