Impact of chromatin structure on sequence variability in the human genome

Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 03/2011; 18(4):510-5. DOI: 10.1038/nsmb.2012
Source: PubMed


DNA sequence variations in individual genomes give rise to different phenotypes within the same species. One mechanism in this process is the alteration of chromatin structure due to sequence variation that influences gene regulation. We composed a high-confidence collection of human single-nucleotide polymorphisms and indels based on analysis of publicly available sequencing data and investigated whether the DNA loci associated with stable nucleosome positions are protected against mutations. We addressed how the sequence variation reflects the occupancy profiles of nucleosomes bearing different epigenetic modifications on genome scale. We found that indels are depleted around nucleosome positions of all considered types, whereas single-nucleotide polymorphisms are enriched around the positions of bulk nucleosomes but depleted around the positions of epigenetically modified nucleosomes. These findings indicate an increased level of conservation for the sequences associated with epigenetically modified nucleosomes, highlighting complex organization of the human chromatin.

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    • "Furthermore, in differentiating murine ESCs (embryonic stem cells), Htz1 deposition increases chromatin accessibility [12]. H2A.Z also has immunology-related functions, showing a specific distribution pattern around the genome variation sites in human CD4+ T cells [13]. "
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    ABSTRACT: Histone variant Htz1 substitution for H2A plays important roles in diverse DNA transactions. Histone chaperones Chz1 and Nap1 (nucleosome assembly protein 1) are important for the deposition Htz1 into nucleosomes. In literatures, it was suggested that Chz1 is a Htz1-H2B-specific chaperone, and it is relatively unstructured in solution but it becomes structured in complex with the Htz1-H2B histone dimer. Nap1 (nucleosome assembly protein 1) can bind (H3-H4)2 tetramers, H2A-H2B dimers and Htz1-H2B dimers. Nap1 can bind H2A-H2B dimer in the cytoplasm and shuttles the dimer into the nucleus. Moreover, Nap1 functions in nucleosome assembly by competitively interacting with non-nucleosomal histone-DNA. However, the exact roles of these chaperones in assembling Htz1-containing nucleosome remain largely unknown. In this paper, we revealed that Chz1 does not show a physical interaction with chromatin. In contrast, Nap1 binds exactly at the genomic DNA that contains Htz1. Nap1 and Htz1 show a preferential interaction with AG-rich DNA sequences. Deletion of chz1 results in a significantly decreased binding of Htz1 in chromatin, whereas deletion of nap1 dramatically increases the association of Htz1 with chromatin. Furthermore, genome-wide nucleosome-mapping analysis revealed that nucleosome occupancy for Htz1p-bound genes decreases upon deleting htz1 or chz1, suggesting that Htz1 is required for nucleosome structure at the specific genome loci. All together, these results define the distinct roles for histone chaperones Chz1 and Nap1 to regulate Htz1 incorporation into chromatin.
    Bioscience Reports 09/2014; 34(5). DOI:10.1042/BSR20140092 · 2.64 Impact Factor
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    • "Nucleosome is the fundamental structural unit of this compaction (1,2), formed by the wrapping of 147-bp double-stranded DNA in 1 and ¾ left-handed superhelix around a histone octamer (3). The presence of histone proteins determines the accessibility of DNA to other interacting proteins and plays a role in altering mutation rate (4), in determining exon architecture (5) and in regulation of transcription (6,7). "
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    ABSTRACT: Nucleosome organization plays a key role in the regulation of gene expression. However, despite the striking advances in the accuracy of nucleosome maps, there are still severe discrepancies on individual nucleosome positioning and how this influences gene regulation. The variability among nucleosome maps, which precludes the fine analysis of nucleosome positioning, might emerge from diverse sources. We have carefully inspected the extrinsic factors that may induce diversity by the comparison of microccocal nuclease (MNase)-Seq derived nucleosome maps generated under distinct conditions. Furthermore, we have also explored the variation originated from intrinsic nucleosome dynamics by generating additional maps derived from cell cycle synchronized and asynchronous yeast cultures. Taken together, our study has enabled us to measure the effect of noise in nucleosome occupancy and positioning and provides insights into the underlying determinants. Furthermore, we present a systematic approach that may guide the standardization of MNase-Seq experiments in order to generate reproducible genome-wide nucleosome patterns.
    Nucleic Acids Research 02/2014; 42(8). DOI:10.1093/nar/gku165 · 9.11 Impact Factor
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    • "Sequencing of multiple cancer genomes has revealed that mutations accumulate at much higher levels in compact, H3K9me3- rich heterochromatin domains (Schuster-Bö ckler and Lehner, 2012), consistent with the slower rates of DNA repair reported in heterochromatin (Goodarzi et al., 2008; Noon et al., 2010). Further, inserts and deletions are depleted around nucleosomes, whereas mutations tend to cluster on the nucleosomal DNA (Chen et al., 2012; Sasaki et al., 2009; Tolstorukov et al., 2011), and both can be influenced by the presence of specific epigenetic modifications on the nucleosome (Schuster-Bö ckler and Lehner, 2012; Tolstorukov et al., 2011). Some of these differences in mutation rates may accrue by negative selection (for example, selection against mutations in coding regions) or through protection of the DNA from mutagens by association with nucleosomes. "
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    ABSTRACT: DNA double-strand breaks (DSBs) can arise from multiple sources, including exposure to ionizing radiation. The repair of DSBs involves both posttranslational modification of nucleosomes and concentration of DNA-repair proteins at the site of damage. Consequently, nucleosome packing and chromatin architecture surrounding the DSB may limit the ability of the DNA-damage response to access and repair the break. Here, we review early chromatin-based events that promote the formation of open, relaxed chromatin structures at DSBs and that allow the DNA-repair machinery to access the spatially confined region surrounding the DSB, thereby facilitating mammalian DSB repair.
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