Mechanisms of chromate carcinogenesis by chromatin alterations.

In a dynamic environment, organisms must constantly mount an adaptive response to new environmental conditions in order to survive. Novel patterns of gene expression, driven by attendant changes in chromatin architecture, aid in adaptation and survival. Critical mechanisms in the control of gene transcription govern new spatiotemporal chromatin-chromatin interactions that make regulatory DNA elements accessible to the transcription factors that control the response.

The aryl hydrocarbon receptor directs the differentiation of murine progenitor blastomeres.

Key regulatory decisions during cleavage divisions in mammalian embryogenesis determine the fate of preimplantation embryonic cells. Single-cell RNA sequencing of early-stage-2-cell, 4-cell, and 8-cell-blastomeres show that the aryl hydrocarbon receptor (AHR), traditionally considered as an environmental sensor, directs blastomere differentiation. Disruption of AHR functions in Ahr knockout embryos or in embryos from dams exposed to dioxin, the prototypic xenobiotic AHR agonist, significantly impairs blastocyst formation, causing repression and loss of transcriptional heterogeneity of OCT4 and CDX2 and incidence of nonspecific downregulation of pluripotency.

Hexavalent chromium disrupts chromatin architecture.

Accessibility of DNA elements and the orchestration of spatiotemporal chromatin-chromatin interactions are critical mechanisms in the regulation of gene transcription. Thus, in an ever-changing milieu, cells mount an adaptive response to environmental stimuli by modulating gene expression that is orchestrated by coordinated changes in chromatin architecture. Correspondingly, agents that alter chromatin structure directly impact transcriptional programs in cells.

Converging Roles of the Aryl Hydrocarbon Receptor in Early Embryonic Development, Maintenance of Stemness, and Tissue Repair.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor well-known for its adaptive role as a sensor of environmental toxicants and mediator of the metabolic detoxification of xenobiotic ligands. In addition, a growing body of experimental data has provided indisputable evidence that the AHR regulates critical functions of cell physiology and embryonic development. Recent studies have shown that the naïve AHR-that is, unliganded to xenobiotics but activated endogenously-has a crucial role in maintenance of embryonic stem cell pluripotency, tissue repair, and regulation of cancer stem cell stemness.

Hexavalent chromium promotes differential binding of CTCF to its cognate sites in Euchromatin.

Hexavalent chromium compounds are well-established respiratory carcinogens to which humans are commonly exposed in industrial and occupational settings. In addition, natural and anthropogenic sources of these compounds contribute to the exposure of global populations through multiple routes, including dermal, ingestion and inhalation that elevate the risk of cancer by largely unresolved mechanisms. Cr(VI) has genotoxic properties that include ternary adduct formation with DNA, increases in DNA damage, mostly by double-strand break formation, and altered transcriptional responses.

Chromium exposure disrupts chromatin architecture upsetting the mechanisms that regulate transcription.

This mini-review highlights current evidence on the mechanisms through which hexavalent chromium (Cr(VI)) disrupts transcriptional regulation, an emerging area of interest and one of the central processes by which chromium induces carcinogenesis. Several studies have shown that Cr(VI) causes widespread DNA damage and disrupts epigenetic signatures, suggesting that chromatin may be a direct Cr(VI) target. The findings discussed here suggest that Cr(VI) disrupts transcriptional regulation by causing genomic architecture changes.