Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Structural variation-induced changes of chromatin architecture and gene expression

ABSTRACT: Copy number variants (CNVs) influence the expression of genes that map not only within the rearrangement, but also to its flanks. To assess the possible mechanism(s) underlying this “neighboring effect”, we compared intrachromosomal interactions and histone modifications in cell lines of patients affected by genomic disorders and control individuals. Using chromosome conformation capture (4C-seq), we observed that a set of genes flanking the Williams-Beuren Syndrome critical region (WBSCR) were often looping together, possibly forming an interacting cluster with each other and the WBSCR. Deletion of the WBSCR disrupts the expression of this group of flanking genes, as well as long-range interactions between them and the rearranged interval. We also pinpointed concomitant changes in histone modifications between samples.We conclude that large genomic rearrangements can lead to chromatin conformation changes that extend far away from the structural variant, thereby possibly modulating expression globally and modifying the phenotype. For example, we determined that the chromatin conformation, histone marks and relative expression levels of the flanking AUTS2 gene, mutations of which are associated with autism and intellectual disabilities, are modified in cell lines from Williams-Beuren syndrome patients. Examination of 4C-seq interaction profile of seven different genes (of which three in duplicate) in 2 different cell lines.

ORGANISM(S): Homo sapiens

SUBMITTER: Marion LELEU

PROVIDER: E-GEOD-33867 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The spatial organization of genes in the interphase nucleus plays an important role in establishment and regulation of gene expression. Contradicting results have been reported to date, with little consensus about the dynamics of nuclear organization and the features of the contact loci. In this study we investigated the properties and dynamics of genomic loci that are in contact with glucocorticoid receptor (GR)-responsive loci. We took a systematic approach, combining genome-wide interaction profiling by the chromosome conformation capture-on-chip (4C) technology with expression, protein occupancy, and chromatin accessibility profiles. This approach allowed a comprehensive analysis of how distinct features of the linear genome are organized in the three-dimensional nuclear space in the context of rapid gene regulation. We found that the transcriptional response to GR occurs without dramatic nuclear reorganization. Moreover, contrary to the view of transcription-driven organization, even genes with opposite transcriptional responses co-localize. Regions contacting GR-regulated genes are not particularly enriched for GR-regulated loci or for any functional group of genes, suggesting that these subnuclear environments are not organized to respond to a specific factor. The contact regions are, however, highly enriched for DNaseI hypersensitive sites which represent the entire cell type-specific regulatory sites. These findings indicate that the nucleus is pre-organized in a conformation allowing rapid transcriptional reprogramming, and suggest that a major force in shaping genome architecture is the repertoire of chromatin binding factors. Numerous open chromatin loci may be arranged in nuclear domains that are poised to respond to diverse signals in general, and to permit efficient gene regulation. Fourteen arrays total: Eight microarrays from individual biological replicates, and six microarrays each from a pool of two biological replicates. This submission represents the chromosome conformation capture-on-chip component of the study. The expression data are included in GSE26189.

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Structural variation-induced changes of chromatin architecture and gene expression

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