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BMC Genomics. 2019 Jan 22;20(1):71. doi: 10.1186/s12864-019-5450-6.

Transcriptionally induced enhancers in the macrophage immune response to Mycobacterium tuberculosis infection.

Author information

1
Massey University, Institute of Natural and Mathematical Sciences, Albany, Auckland, New Zealand.
2
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.
3
International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.
4
Gene Expression and Biophysics Group, CSIR Synthetic Biology ERA, Pretoria, South Africa.
5
Division of Chemical Systems and Synthetic Biology, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa.
6
Gene Expression and Biophysics Unit, Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal.
7
Division of Genomic Technologies, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.
8
Massey University, Institute of Natural and Mathematical Sciences, Albany, Auckland, New Zealand. s.schmeier@massey.ac.nz.

Abstract

BACKGROUND:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Macrophages; Transcriptional enhancers; Transcriptional regulation; Tuberculosis; eRNA

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