Chromatin structure in cancer

Abstract

In the past decade, we have seen the emergence of sequence-based methods to understand chromosome organization. With the confluence of in situ approaches to capture information on looping, topological domains, and larger chromatin compartments, understanding chromatin-driven disease is becoming feasible. Excitingly, recent advances in single molecule imaging with capacity to reconstruct “bulk-cell” features of chromosome conformation have revealed cell-to-cell chromatin structural variation. The fundamental question motivating our analysis of the literature is, can altered chromatin structure drive tumorigenesis? As our community learns more about rare disease, including low mutational frequency cancers, understanding “chromatin-driven” pathology will illuminate the regulatory structures of the genome. We describe recent insights into altered genome architecture in human cancer, highlighting multiple pathways toward disruptions of chromatin structure, including structural variation, noncoding mutations, metabolism, and de novo mutations to architectural regulators themselves. Our analysis of the literature reveals that deregulation of genome structure is characteristic in distinct classes of chromatin-driven tumors. As we begin to integrate the findings from single cell imaging studies and chromatin structural sequencing, we will be able to understand the diversity of cells within a common diagnosis, and begin to define structure–function relationships of the misfolded genome.

Global chromatin reorganization and regulation of genes with specific evolutionary ages during differentiation and cancer

“…Gene regulation, especially through polycomb binding, has been strongly associated with the 3D chromatin structure inside the nucleus, which was shown to be deeply compromised in polycomb units mutants (Schoenfelder et al, 2015). Chromatin organization is known to be dramatically re-organised both in cell differentiation through lineage definition (Freire-Pritchett et al, 2017), and in cancer (Deng et al, 2022; Wang et al, 2022). This led us to investigate whether gene evolutionary ages might also be associated with gene localisations across the 3D genome conformation.…”

FASTKD1 is a diagnostic and prognostic biomarker for STAD associated with m6A modification and immune infiltration

“…Structural variations, ampli cations, deletions, and rearrangements in particular chromosomal regions are associated with different types of tumors, these changes bring about alterations in gene dosage, disruption of regulatory elements, and activation or inactivation of oncogenes and tumor suppressor genes, found within these regions. These alterations lead to uncontrolled growth and survival of cells and promote the development and progression of tumors (Wang et al, 2022). Catalytic activity speci cally acting on RNA includes enzymes involved in processing, modi cation, and degradation, dysregulation of these enzymatic activities can affect critical cellular processes, including the stability, translation, and splicing of mRNA.…”

The 3D chromatin landscape of rhabdomyosarcoma

“…For example, our evidence suggests that there exists excessive interaction between CGGBP1 on chr3 and ATP8A2 on chr13 in SMS-CTR cell line ( Supplementary Figure S11 ). Long-read RNA-sequencing and high content-imaging (26,70) will be efficacious in further studies of potential fusion driver events of embryonal RMS, to expand the scope of known alterations in this tumor. Moreover, future studies will be impactful for domain-specific normalizations in the context of spike-in chromatin ( Supplementary Figure S12 ).…”

“…We sought to characterize genome structure-function relationships in RMS at several unique levels, including (i) larger (> Mb-scale) structural contact domains termed compartments (19)(20)(21), (ii) medium-range contact domains (< Mb-scale), or topologically associating domains (TADs) (19,22,23), (iii) in the context of the interactivity of copy number variation (CNV), and structural variations (SV) (24)(25)(26)(27) and (iv) at the level of the gene regulatory loci encoding the major fusion oncogenes in FP-RMS (28). In our comparative analyses we discover substantial unique or subtype-specific regions at the compartment level (>1Mb) amid convergence in epigenetic conservation of FP-RMS and FN-RMS genomes.…”