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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Available from: Robert M Stephens
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    • "Associations between chromatin structure and constraints on gene evolution can arise as a byproduct of the link between chromatin structure and gene expression patterns (Prendergast et al. 2007; Filion et al. 2010; Kharchenko et al. 2011). Variation in mutation rate and sequence constraints are also linked to nucleosome positioning and chromatin accessibility (Prendergast et al. 2007; Prendergast and Semple 2011; Tolstorukov et al. 2011; Schuster- Bockler and Lehner 2012; Langley et al. 2014; Makova and Hardison 2015). However, this issue has yet to be investigated in insect genomes, where evolutionary variation in DNA methylation (Glastad et al. 2011) provides the opportunity to disentangle the relative effects of DNA methylation and other epigenetic marks. "

    Preview · Article · Dec 2015 · G3-Genes Genomes Genetics
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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.
    Full-text · Article · Sep 2014 · Bioscience Reports
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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.
    Full-text · Article · Feb 2014 · Nucleic Acids Research
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