Mycobacterium tuberculosis infection triggers epigenetic changes that are enriched in a type I IFN signature

Katrina Madden; Rayan El Hamra; Stefania Berton; Jake Felker; Gonzalo G Alvarez; Alexandre Blais; Jim Sun

doi:10.1093/femsml/uqad006

Mycobacterium tuberculosis infection triggers epigenetic changes that are enriched in a type I IFN signature

Microlife. 2023 Feb 6:4:uqad006. doi: 10.1093/femsml/uqad006. eCollection 2023.

Authors

Katrina Madden^{1

2}, Rayan El Hamra^{1

2}, Stefania Berton^{1

2}, Jake Felker¹, Gonzalo G Alvarez^{3

4

5}, Alexandre Blais^{1

2

6

7}, Jim Sun^{1

2}

Affiliations

¹ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
² Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
³ Ottawa Hospital Research Institute, Ottawa, Ontario K1Y 4E9, Canada.
⁴ School of Public Health, University of Ottawa, Ottawa, Ontario K1G 5Z3, Canada.
⁵ Division of Respirology, Department of Medicine, The Ottawa Hospital, Ottawa, Ontario K1H 8L6, Canada.
⁶ Ottawa Institute of Systems Biology, Ottawa, Ontario K1H 8M5, Canada.
⁷ Éric Poulin Centre for Neuromuscular Disease, Ottawa, Ontario K1H 8M5, Canada.

Abstract

Tuberculosis, a deadly infectious lung disease caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of bacterial disease-related deaths worldwide. Mtb reprograms and disables key antibacterial response pathways, many of which are regulated by epigenetic mechanisms that control the accessibility of chromatin to the transcriptional machinery. Recent reports suggest that host phosphatases, such as PPM1A, contribute to regulating chromatin accessibility during bacterial infections. However, changes in genome-wide chromatin accessibility during Mtb infection and whether PPM1A plays a role in this process remains unknown. Herein, we use combinatorial chromatin accessibility (ATAC-seq) and transcriptomic (RNA-seq) profiling of wild-type, PPM1A knockout and PPM1A overexpressing macrophages to demonstrate that Mtb infection induces global chromatin remodelling consistent with changes in gene expression. The strongest concordant changes to chromatin accessibility and gene expression triggered by Mtb infection were enriched for genes involved in type I interferon (IFN) signalling pathways. A panel of 15 genes with the strongest concordant changes in chromatin accessibility and gene expression were validated to be significantly upregulated in Mtb-infected human monocyte-derived macrophages. PPM1A expression affects chromatin accessibility profiles during Mtb infection that are reflected in the total number, chromosome location, and directionality of change. Transcription factor binding motif analysis revealed enrichment for transcription factors involved in the type I IFN pathway during Mtb infection, including members of the IRF, MEF2, and AP-1 families. Our study shows that altered type I IFN responses in Mtb-infected macrophages occur due to genome-wide changes in chromatin accessibility, and that PPM1A could influence a subset of these signatures.

Keywords: ATAC-seq; Mycobacterium tuberculosis; RNA-seq; chromatin accessibility; epigenome; host-directed therapy; transcriptome; tuberculosis; type I IFN.