Functional interactions between Mi-2β and AP1 complexes control response and recovery from barrier disruption

Keratinocytes respond to environmental signals by eliciting induction of genes that preserve skin’s integrity. Here we show that the transcriptional response to stress signaling is supported by short-lived epigenetic changes. Comparison of chromatin accessibility and transcriptional changes induced by barrier disruption or by loss of the nucleosome remodeler Mi-2β identified their striking convergence in mouse and human keratinocytes. Mi-2β directly repressed genes induced by barrier disruption by restricting AP1-enriched promoter-distal sites, occupied by Mi-2β and JUNB at steady state and by c-JUN after Mi-2β depletion or stress signaling. Barrier disruption led to a modest reduction in Mi-2β expression and a further selective reduction of Mi-2β localization at stress response genes possibly through competition with activated c-JUN. Consistent with a repressive role at stress response genes, genetic ablation of Mi-2β did not prevent re-establishment of barrier integrity but was required for return to homeostasis. Thus a competition between Mi-2β repressive and activating AP1 complexes may permit rapid transcriptional response to and resolution from stress signaling. 24 mRNA-seq, 8 ATAC-seq, 22 ChIP_seq samples

角质形成细胞（Keratinocytes）可通过诱导维持皮肤完整性的基因，响应环境信号。本研究发现，应激信号介导的转录应答依赖于短暂性表观遗传修饰变化。通过对比屏障破坏或核小体重塑因子Mi-2β缺失所诱导的染色质可及性与转录组变化，我们发现二者在小鼠与人类角质形成细胞中存在显著的趋同效应。Mi-2β可通过限制富集激活蛋白1（AP1）的启动子远端区域，直接抑制屏障破坏诱导的基因；该区域在稳态下由Mi-2β与JUNB共同占据，而在Mi-2β缺失或应激信号激活后则结合c-JUN。屏障破坏可使Mi-2β的表达出现轻度下调，并可能通过与活化c-JUN竞争，进一步选择性降低Mi-2β在应激应答基因位点的定位。与Mi-2β在应激应答基因中的抑制性功能一致，Mi-2β的基因敲除并不会阻碍皮肤屏障完整性的重建，但却是恢复体内稳态所必需的。由此可见，Mi-2β抑制性复合物与激活型AP1复合物之间的竞争，可介导对应激信号的快速转录应答，并能在应激解除后恢复转录稳态。本数据集包含24个mRNA测序（mRNA-seq）样本、8个转座酶可及性染色质测序（ATAC-seq）样本以及22个染色质免疫共沉淀测序（ChIP-seq）样本。