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, RNAseq 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.

Capturing cell type-specific chromatin compartment patterns by applying topic modeling to single-cell Hi-C data

“…Previous studies [ 36 , 37 ] have shown an enrichment of B-to-A compartment reorganization from one cell type to another in regions with upregulated genes. Therefore, we asked if the B-to-A transitions were enriched in regions containing upregulated marker genes associated with the cell types in our datasets.…”

Integration of Mutational Signature Analysis with 3D Chromatin Data Unveils Differential AID-Related Mutagenesis in Indolent Lymphomas

“…Because mutagenesis and chromatin conformation are dynamic processes, future systematic analyses over time may be desirable to refine the results of this study. Nevertheless, the folding patterns of chromatin compartment domains are highly conserved within B-cells, and even during malignant B-cell transformation, gene switching from the active to the inactive compartment was only 3.1% [ 55 ]. Whether specific chromatin organizations affecting CLL and FL may alter our findings, remains unanswered and will require technically challenging Hi-C experiments on human primary lymphoma cells.…”

The Many Faces of Gene Regulation in Cancer: A Computational Oncogenomics Outlook

“…Later, two studies [34,222] reported that upon activation of the ER-alpha, transcriptional changes entail coordinated responses at the chromatin structure level. Finally, Hi-C experiments of genome-wide chromatin interactions have identified a switch from B to A compartments accompanied by up-regulation of their resident genes in breast cancer [223] and B-cell lymphoma [224].…”