Histone acetylome-wide association study of tuberculosis

del Rosario, R. C. H.; Poschmann, J.; Kumar, P.; Cheng, C. Y.; Ong, S. T.; Hajan, H. S.; Kumar, D.; Marzuki, M.; Lu, X.; Lee, A.; Tang, Y.; Chee, C. B. E.; Lim, C.; Lee, B.; Lum, J.; Zolezzi, F.; Poidinger, M.; Rotzschke, O.; Khor, C. C.; Wang, Y. T.; Chandy, K. G.; De Libero, G.; Singhal, A.; Prabhakar, S.

doi:10.1101/644112

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bioRxiv · 10.1101/644112

Histone acetylome-wide association study of tuberculosis

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Abstract

Host-cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here, we describe the first histone acetylome-wide association study (HAWAS) of an infectious disease, based on genome-wide H3K27 acetylation profiling of peripheral granulocytes and monocytes from subjects with active Mycobacterium tuberculosis (Mtb) infection and healthy controls. We detected >2,000 differentially acetylated loci in either cell type in a Chinese discovery cohort, which were validated in a subsequent multi-ethnic cohort, thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression in a third cohort. Differential acetylation was enriched near potassium channel genes, including KCNJ15, which modulated Akt-mTOR signaling and promoted Mtb clearance in vitro. We performed histone acetylation QTL analysis on the dataset and identified candidate causal variants for immune phenotypes. Our study serves as proof-of-principle for HAWAS to infer mechanisms of host response to pathogens.

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del Rosario, R. C. H., Poschmann, J., Kumar, P., Cheng, C. Y., Ong, S. T., Hajan, H. S., Kumar, D., Marzuki, M., Lu, X., Lee, A., Tang, Y., Chee, C. B. E., Lim, C., Lee, B., Lum, J., Zolezzi, F., Poidinger, M., Rotzschke, O., Khor, C. C., Wang, Y. T., Chandy, K. G., De Libero, G., Singhal, A., Prabhakar, S.. 2019-05-21. Histone acetylome-wide association study of tuberculosis. https://doi.org/10.1101/644112

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