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首页> 外文期刊>Molecular and Cellular Biology >Chromium Cross-Links Histone Deacetylase 1-DNA Methyltransferase 1 Complexes to Chromatin, Inhibiting Histone-Remodeling Marks Critical for Transcriptional Activation
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Chromium Cross-Links Histone Deacetylase 1-DNA Methyltransferase 1 Complexes to Chromatin, Inhibiting Histone-Remodeling Marks Critical for Transcriptional Activation

机译：铬交联组蛋白去乙酰化酶1-DNA甲基转移酶1络合物对染色质，抑制组蛋白重塑标记对于转录激活至关重要。

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Transcriptional regulation of gene expression requires posttranslational modification of histone proteins, which, in concert with chromatin-remodeling factors, modulate chromatin structure. Exposure to environmental agents may interfere with specific histone modifications and derail normal patterns of gene expression. To test this hypothesis, we coexposed cells to binary mixtures of benzo[a]pyrene (B[a]P), an environmental procarcinogen that activates Cyp1a1 transcriptional responses mediated by the aryl hydrocarbon receptor (AHR), and chromium, a carcinogenic heavy metal that represses B[a]P-inducible AHR-mediated gene expression. We show that chromium cross-links histone deacetylase 1-DNA methyltransferase 1 (HDAC1-DNMT1) complexes to Cyp1a1 promoter chromatin and inhibits histone marks induced by AHR-mediated gene transactivation, including phosphorylation of histone H3 Ser-10, trimethylation of H3 Lys-4, and various acetylation marks in histones H3 and H4. These changes inhibit RNA polymerase II recruitment without affecting the kinetics of AHR DNA binding. HDAC1 and DNMT1 inhibitors or depletion of HDAC1 or DNMT1 with siRNAs blocks chromium-induced transcriptional repression by decreasing the interaction of these proteins with the Cyp1a1 promoter and allowing histone acetylation to proceed. By inhibiting Cyp1a1 expression, chromium stimulates the formation of B[a]P DNA adducts. Epigenetic modification of gene expression patterns may be a key element of the developmental and carcinogenic outcomes of exposure to chromium and to other environmental agents.
机译：基因表达的转录调节需要组蛋白的翻译后修饰，与染色质重塑因子协同调节染色质结构。暴露于环境因素下可能会干扰特定的组蛋白修饰并破坏正常的基因表达模式。为了验证这一假设，我们将细胞与苯并[ a ] py的二元混合物共暴露（B [ a ] P），这是一种激活 Cyp1a1 a ] P诱导的AHR介导的基因表达）介导的em>转录反应。我们显示铬使 Cyp1a1 启动子染色质交联组蛋白脱乙酰基酶1-DNA甲基转移酶1（HDAC1-DNMT1）复合物，并抑制由AHR介导的基因反式激活（包括组蛋白H3 Ser-的磷酸化）诱导的组蛋白标记。 10，H3 Lys-4的三甲基化，以及组蛋白H3和H4中的各种乙酰化标记。这些变化抑制了RNA聚合酶II的募集而没有影响AHR DNA结合的动力学。 HDAC1和DNMT1抑制剂或siRNA耗尽HDAC1或DNMT1可以通过减少这些蛋白与 Cyp1a1 启动子的相互作用并允许组蛋白乙酰化来阻止铬诱导的转录抑制。通过抑制Cyp1a1的表达，铬刺激了B [ a ] P DNA加合物的形成。基因表达模式的表观遗传修饰可能是暴露于铬和其他环境因素导致发育和致癌结果的关键因素。

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