Dataset Information

Analyzing the 3D chromatin organization coordinating with gene expression regulation in B-cell lymphoma.

ABSTRACT: BACKGROUND:Eukaryotes compact chromosomes densely and non-randomly, forming three-dimensional structures. Alterations of the chromatin structures are often associated with diseases. In particular, aggressive cancer development from the disruption of the humoral immune system presents abnormal gene regulation which is accompanied by chromatin reorganizations. How the chromatin structures orchestrate the gene expression regulation is still poorly understood. Herein, we focus on chromatin dynamics in normal and abnormal B cell lymphocytes, and investigate its functional impact on the regulation of gene expression. METHODS:We conducted an integrative analysis using publicly available multi-omics data that include Hi-C, RNA-seq and ChIP-seq experiments with normal B cells, lymphoma and ES cells. We processed and re-analyzed the data exhaustively and combined different scales of genome structures with transcriptomic and epigenetic features. RESULTS:We found that the chromatin organizations are highly preserved among the cells. 5.2% of genes at the specific repressive compartment in normal pro-B cells were switched to the permissive compartment in lymphoma along with increased gene expression. The genes are involved in B-cell related biological processes. Remarkably, the boundaries of topologically associating domains were not enriched by CTCF motif, but significantly enriched with Prdm1 motif that is known to be the key factor of B-cell dysfunction in aggressive lymphoma. CONCLUSIONS:This study shows evidence of a complex relationship between chromatin reorganization and gene regulation. However, an unknown mechanism may exist to restrict the structural and functional changes of genomic regions and cognate genes in a specific manner. Our findings suggest the presence of an intricate crosstalk between the higher-order chromatin structure and cancer development.

SUBMITTER: Nagai LAE

PROVIDER: S-EPMC7402584 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Analyzing the 3D chromatin organization coordinating with gene expression regulation in B-cell lymphoma.

Nagai Luis Augusto Eijy LAE Park Sung-Joon SJ Nakai Kenta K

BMC medical genomics 20190320 Suppl 7

<h4>Background</h4>Eukaryotes compact chromosomes densely and non-randomly, forming three-dimensional structures. Alterations of the chromatin structures are often associated with diseases. In particular, aggressive cancer development from the disruption of the humoral immune system presents abnormal gene regulation which is accompanied by chromatin reorganizations. How the chromatin structures orchestrate the gene expression regulation is still poorly understood. Herein, we focus on chromatin d ...[more]

PMID: 30894186

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Project description:BACKGROUND:Genome-wide ligation-based assays such as Hi-C provide us with an unprecedented opportunity to investigate the spatial organization of the genome. Results of a typical Hi-C experiment are often summarized in a chromosomal contact map, a matrix whose elements reflect the co-location frequencies of genomic loci. To elucidate the complex structural and functional interactions between those genomic loci, networks offer a natural and powerful framework. RESULTS:We propose a novel graph-theoretical framework, the Corrected Gene Proximity (CGP) map to study the effect of the 3D spatial organization of genes in transcriptional regulation. The starting point of the CGP map is a weighted network, the gene proximity map, whose weights are based on the contact frequencies between genes extracted from genome-wide Hi-C data. We derive a null model for the network based on the signal contributed by the 1D genomic distance and use it to "correct" the gene proximity for cell type 3D specific arrangements. The CGP map, therefore, provides a network framework for the 3D structure of the genome on a global scale. On human cell lines, we show that the CGP map can detect and quantify gene co-regulation and co-localization more effectively than the map obtained by raw contact frequencies. Analyzing the expression pattern of metabolic pathways of two hematopoietic cell lines, we find that the relative positioning of the genes, as captured and quantified by the CGP, is highly correlated with their expression change. We further show that the CGP map can be used to form an inter-chromosomal proximity map that allows large-scale abnormalities, such as chromosomal translocations, to be identified. CONCLUSIONS:The Corrected Gene Proximity map is a map of the 3D structure of the genome on a global scale. It allows the simultaneous analysis of intra- and inter- chromosomal interactions and of gene co-regulation and co-localization more effectively than the map obtained by raw contact frequencies, thus revealing hidden associations between global spatial positioning and gene expression. The flexible graph-based formalism of the CGP map can be easily generalized to study any existing Hi-C datasets.

Project description:BACKGROUND:Our appreciation of the critical role of the genome's 3D organization in gene regulation is steadily increasing. Recent 3C-based deep sequencing techniques elucidated a hierarchy of structures that underlie the spatial organization of the genome in the nucleus. At the top of this hierarchical organization are chromosomal territories and the megabase-scale A/B compartments that correlate with transcriptional activity within cells. Below them are the relatively cell-type-invariant topologically associated domains (TADs), characterized by high frequency of physical contacts between loci within the same TAD, and are assumed to function as regulatory units. Within TADs, chromatin loops bring enhancers and target promoters to close spatial proximity. Yet, we still have only rudimentary understanding how differences in chromatin organization between different cell types affect cell-type-specific gene expression programs that are executed under basal and challenged conditions. RESULTS:Here, we carried out a large-scale meta-analysis that integrated Hi-C data from thirteen different cell lines and dozens of ChIP-seq and RNA-seq datasets measured on these cells, either under basal conditions or after treatment. Pairwise comparisons between cell lines demonstrate a strong association between modulation of A/B compartmentalization, differential gene expression and transcription factor (TF) binding events. Furthermore, integrating the analysis of transcriptomes of different cell lines in response to various challenges, we show that A/B compartmentalization of cells under basal conditions significantly correlates not only with gene expression programs and TF binding profiles that are active under the basal condition but also with those induced in response to treatment. Yet, in pairwise comparisons between different cell lines, we find that a large portion of differential TF binding and gene induction events occur in genomic loci assigned to A compartment in both cell types, underscoring the role of additional critical factors in determining cell-type-specific transcriptional programs. CONCLUSIONS:Our results further indicate the role of dynamic genome organization in regulation of differential gene expression between different cell types and the impact of intra-TAD enhancer-promoter interactions that are established under basal conditions on both the basal and treatment-induced gene expression programs.

Dataset Information

Analyzing the 3D chromatin organization coordinating with gene expression regulation in B-cell lymphoma.

Publications

Analyzing the 3D chromatin organization coordinating with gene expression regulation in B-cell lymphoma.

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