The heterogeneity of respirable particulates and compounds complicates our understanding of transcriptional responses to air pollution. Here, we address this by applying precision nuclear run-on sequencing and the assay for transposase-accessible chromatin sequencing to measure nascent transcription and chromatin accessibility in airway epithelial cells after wood smoke particle (WSP) exposure. We used transcription factor enrichment analysis to identify temporally distinct roles for ternary response factor-serum response factor complexes, the aryl hydrocarbon receptor (AHR), and NFκB in regulating transcriptional changes induced by WSP. Transcription of canonical targets of the AHR, such as CYP1A1 and AHRR, was robustly increased after just 30 min of WSP exposure, and we discovered novel AHR-regulated pathways and targets including the DNA methyltransferase, DNMT3L. Transcription of these genes and associated enhancers rapidly returned to near baseline by 120 min after exposure. The kinetics of AHR- and NFκB-regulated responses to WSP were distinguishable based on the timing of both transcriptional responses and chromatin remodeling, with induction of several cytokines implicated in maintaining NFκB-mediated responses through 120 min of exposure. In aggregate, our data establish a direct and primary role for AHR in mediating airway epithelial responses to WSP and identify crosstalk between AHR and NFκB signaling in controlling proinflammatory gene expression. This work also defines an integrated genomics-based strategy for deconvoluting multiplexed transcriptional responses to heterogeneous environmental exposures.

中文翻译：

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对木材烟雾颗粒的多重转录反应的解卷积定义了快速芳烃受体信号动力学。

可呼吸颗粒和化合物的异质性使我们对空气污染转录反应的理解变得复杂。在这里，我们通过应用精确核连续测序和转座酶可及染色质测序测定法来测量木烟颗粒（WSP）暴露后气道上皮细胞的新生转录和染色质可及性来解决这个问题。我们使用转录因子富集分析来确定三元反应因子-血清反应因子复合物、芳烃受体 (AHR) 和 NFκB 在调节 WSP 诱导的转录变化中的不同时间作用。在 WSP 暴露仅 30 分钟后，AHR 经典靶标（例如 CYP1A1 和 AHRR）的转录就大幅增加，并且我们发现了新的 AHR 调节途径和靶标，包括 DNA 甲基转移酶 DNMT3L。这些基因和相关增强子的转录在暴露后 120 分钟迅速恢复到接近基线。AHR 和 NFκB 调节的 WSP 反应动力学根据转录反应和染色质重塑的时间进行区分，并诱导多种细胞因子参与在 120 分钟的暴露下维持 NFκB 介导的反应。总的来说，我们的数据确定了 AHR 在介导气道上皮对 WSP 反应中的直接和主要作用，并确定了 AHR 和 NFκB 信号传导在控制促炎基因表达中的串扰。这项工作还定义了一种基于基因组学的整合策略，用于解卷积对异质环境暴露的多重转录反应。