Hexavalent chromium disrupts chromatin architecture

Abstract

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. Heavy metals, including hexavalent chromium (Cr(VI)), are of special interest because of their ability to interact directly with cellular protein, DNA and other macromolecules, resulting in general damage or altered function. In this review we highlight the chromium-mediated mechanisms that promote disruption of chromatin architecture and how these processes are integral to its carcinogenic properties. Emerging evidence shows that Cr(VI) targets nucleosomal architecture in euchromatin, particularly in genomic locations flanking binding sites of the essential transcription factors CTCF and AP1. Ultimately, these changes contribute to an altered chromatin state in critical gene regulatory regions, which disrupts gene transcription in functionally relevant biological processes.

Keywords: Chromatin architecture; Gene transcription; Hexavalent chromium.

Figure 1:

The biological fate of hexavalent chromium in mammalian cells. Cr(VI) is largely reduced to Cr(III) extracellularly, effectively limiting uptake of Cr(III) by cells and serving as a detoxification mechanism. The remaining Cr(VI), that escapes the extracellular reduction process mimics sulfate or phosphate ions and is transported by sulfate anion transporters into the cell. Once in the cytoplasm, the reduction of Cr(VI) to Cr(III) by antioxidants such as ascorbate, glutathione, and cysteine occurs in a step-wise manner (dependent on the antioxidant) and generates reactive chromium intermediates as well as reactive oxygen species capable of exerting oxidative macromolecular damage. Remnant Cr(VI) is transported to the nucleus, where it is reduced to Cr(III), causing oxidative DNA damage. Cr(III) forms DNA adducts, protein-DNA crosslinks and causes general genomic instability.

Figure 2:

Hexavalent chromium induces diverse chromatin alterations. a) Once Cr(VI) reaches the nucleus, it causes damage through direct oxidation and formation of Cr-DNA adducts. This evokes a DNA damage response that brings alongside it, chromatin structural changes to allow for DNA repair. Additionally, chromium mediates protein-DNA crosslinks that impair protein function. b) Once polymerases encounter these bulky DNA lesions, they largely pause, inducing a state of transcriptional disruption (RNApolII pausing). c) Cr(VI) alters chromatin accessibility in flanking regions of transcription factors CTCF, AP-1 and BACH1. This can be attributed to altered transcription factor binding dynamics, through as-yet unknown mechanisms (d); or by direct nucleosomal displacement (e). Chromium alters nucleosome arrangement, resulting in position shifts and occupancy changes.