Abstract
BackgroundEukaryotes 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.MethodsWe 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.ResultsWe 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.ConclusionsThis 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.
Highlights
Eukaryotes compact chromosomes densely and non-randomly, forming three-dimensional structures
Topologically associating domain (TAD) are highly conserved between cell types and are often delimited by CCCT C-binding factor (CTCF) motifs, our results show the relationship of TAD boundaries with cancer-related transcription factors rather than with CTCF
Our results show that the majority of TADs among pro-B cells, lymphoma and ES cells are highly conserved, whereas specific genomic regions are involved in the compartment change
Summary
Eukaryotes compact chromosomes densely and non-randomly, forming three-dimensional structures. Aggressive cancer development from the disruption of the humoral immune system presents abnormal gene regulation which is accompanied by chromatin reorganizations. To define three-dimensional (3D) chromatin structures in eukaryotic nuclei, Chromosome Conformation Capture (3C) sequencing technologies, such as the genome-wide 3C version (Hi-C), have emerged as a promising strategy and revealed that the 3D structures non-randomly compacted have functional roles for gene expression [1,2,3,4,5]. B cells are central in the humoral immune system, and abnormal gene regulation in the cells is highly associated with cancer development [9]. A recent study [11] using gene expression profiling revealed that PRDM1/ BLIMP-1, a master regulator of plasma-cell differentiation, is inactivated in lymphoma where loss of genetic expression correlates with tumor cell proliferation
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