Department of Environmental and Public Health Sciences and Center for Environmental Genetics University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Epigenetics. 2021 Dec;16(12):1361-1376. doi: 10.1080/15592294.2020.1864168. Epub 2021 Jan 7.
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. Our previous work using ATAC-seq showed that CTCF motifs were enriched in Cr(VI)-dependent differentially accessible chromatin, suggesting that CTCF, a key transcription factor responsible for the regulation of the transcriptome, might be a chromium target. To test this hypothesis, we investigated the effect of Cr(VI) treatment on the binding of CTCF to its cognate sites and ensuing changes in transcription-related histone modifications. Differentially bound CTCF sites were enriched by Cr(VI) treatment within transcription-related regions, specifically transcription start sites and upstream genic regions. Functional annotation of the affected genes highlighted biological processes previously associated with Cr(VI) exposure. Notably, we found that differentially bound CTCF sites proximal to the promoters of this subset of genes were frequently associated with the active histone marks H3K27ac, H3K4me3, and H3K36me3, in agreement with the concept that Cr(VI) targets CTCF in euchromatic regions of the genome. Our results support the conclusion that Cr(VI) treatment promotes the differential binding of CTCF to its cognate sites in genes near transcription-active boundaries, targeting these genes for dysregulation.
六价铬化合物是公认的人类在工业和职业环境中常见的呼吸致癌物质。此外，这些化合物的天然和人为来源通过多种途径，包括皮肤接触、摄入和吸入，导致全球人群暴露，这大大增加了癌症的风险，但其中的机制仍未得到解决。Cr(VI) 具有遗传毒性，包括与 DNA 形成三元加合物、增加 DNA 损伤，主要是双链断裂形成，以及改变转录反应。我们之前使用 ATAC-seq 的工作表明，CTCF 基序在 Cr(VI) 依赖性差异可及染色质中富集，这表明 CTCF 是一种关键的转录因子，负责调节转录组，可能是铬的靶标。为了验证这一假设，我们研究了 Cr(VI) 处理对 CTCF 与其同源结合位点结合的影响，以及随后转录相关组蛋白修饰的变化。Cr(VI) 处理后，差异结合的 CTCF 位点在转录相关区域，特别是转录起始位点和上游基因区域富集。受影响基因的功能注释突出了先前与 Cr(VI) 暴露相关的生物学过程。值得注意的是，我们发现，这组基因启动子附近差异结合的 CTCF 位点通常与活跃的组蛋白标记 H3K27ac、H3K4me3 和 H3K36me3 相关，这与 Cr(VI) 靶向基因组常染色质区 CTCF 的概念一致。我们的研究结果支持了这样的结论，即 Cr(VI) 处理促进了 CTCF 在转录活跃边界附近其同源基因上的差异结合，从而靶向这些基因的失调。
