Massey University, Institute of Natural and Mathematical Sciences, Albany, Auckland, New Zealand.
Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa.
BMC Genomics. 2019 Jan 22;20(1):71. doi: 10.1186/s12864-019-5450-6.
Tuberculosis is a life-threatening infectious disease caused by Mycobacterium tuberculosis (M.tb). M.tb subverts host immune responses to build a favourable niche and survive inside of host macrophages. Macrophages can control or eliminate the infection, if acquire appropriate functional phenotypes. Transcriptional regulation is a key process that governs the activation and maintenance of these phenotypes. Among the factors orchestrating transcriptional regulation during M.tb infection, transcriptional enhancers still remain unexplored.
We analysed transcribed enhancers in M.tb-infected mouse bone marrow-derived macrophages. We established a link between known M.tb-responsive transcription factors and transcriptional activation of enhancers and their target genes. Our data suggest that enhancers might drive macrophage response via transcriptional activation of key immune genes, such as Tnf, Tnfrsf1b, Irg1, Hilpda, Ccl3, and Ccl4. We report enhancers acquiring transcription de novo upon infection. Finally, we link highly transcriptionally induced enhancers to activation of genes with previously unappreciated roles in M.tb infection, such as Fbxl3, Tapt1, Edn1, and Hivep1.
Our findings suggest the importance of macrophage host transcriptional enhancers during M.tb infection. Our study extends current knowledge of the regulation of macrophage responses to M.tb infection and provides a basis for future functional studies on enhancer-gene interactions in this process.
结核病是一种由结核分枝杆菌（M.tb）引起的危及生命的传染病。M.tb 颠覆了宿主的免疫反应，在宿主巨噬细胞内建立了一个有利的小生境并存活下来。如果巨噬细胞获得适当的功能表型，它们可以控制或消除感染。转录调控是一个关键过程，它控制着这些表型的激活和维持。在 M.tb 感染过程中，转录增强子是协调转录调控的因素之一，但仍有待探索。
我们分析了 M.tb 感染的小鼠骨髓来源的巨噬细胞中的转录增强子。我们建立了已知的 M.tb 反应性转录因子与增强子及其靶基因转录激活之间的联系。我们的数据表明，增强子可能通过转录激活关键免疫基因，如 Tnf、Tnfrsf1b、Irg1、Hilpda、Ccl3 和 Ccl4，来驱动巨噬细胞反应。我们报告了感染后增强子获得转录起始的情况。最后，我们将高度转录诱导的增强子与在 M.tb 感染中具有以前未被认识的作用的基因的激活联系起来，如 Fbxl3、Tapt1、Edn1 和 Hivep1。
我们的发现表明，在 M.tb 感染期间，巨噬细胞宿主转录增强子的重要性。我们的研究扩展了目前对巨噬细胞对 M.tb 感染反应的调控的认识，并为未来在这个过程中对增强子-基因相互作用的功能研究提供了基础。
