An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome

Gomez-Gonzalez, P. J., Andreu, N., Phelan, J. E., Florez de Sessions, P., Glynn, J. R., Crampin, A. C. , Campino, S., Butcher, P. D., Hibberd, M. L. and Clark, T. G. (2019) An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome. Scientific Reports, 9, 5204. (doi: 10.1038/s41598-019-41692-2) (PMID:30914757) (PMCID:PMC6435705)

[img]
Preview
Text
177290.pdf - Published Version
Available under License Creative Commons Attribution.

1MB

Abstract

Human tuberculosis disease (TB), caused by Mycobacterium tuberculosis (Mtb), is a complex disease, with a spectrum of outcomes. Genomic, transcriptomic and methylation studies have revealed differences between Mtb lineages, likely to impact on transmission, virulence and drug resistance. However, so far no studies have integrated sequence-based genomic, transcriptomic and methylation characterisation across a common set of samples, which is critical to understand how DNA sequence and methylation affect RNA expression and, ultimately, Mtb pathogenesis. Here we perform such an integrated analysis across 22 M. tuberculosis clinical isolates, representing ancient (lineage 1) and modern (lineages 2 and 4) strains. The results confirm the presence of lineage-specific differential gene expression, linked to specific SNP-based expression quantitative trait loci: with 10 eQTLs involving SNPs in promoter regions or transcriptional start sites; and 12 involving potential functional impairment of transcriptional regulators. Methylation status was also found to have a role in transcription, with evidence of differential expression in 50 genes across lineage 4 samples. Lack of methylation was associated with three novel variants in mamA, likely to cause loss of function of this enzyme. Overall, our work shows the relationship of DNA sequence and methylation to RNA expression, and differences between ancient and modern lineages. Further studies are needed to verify the functional consequences of the identified mechanisms of gene expression regulation.

Item Type:Articles
Additional Information:P.J.G.-G. is funded by an MRC-LID PhD studentship. J.P. is funded by a Newton Institutional Links Grant (British Council. 261868591). T.G.C. is funded by the Medical Research Council UK (Grant Nos MR/M01360X/1, MR/N010469/1, MR/R025576/1, and MR/R020973/1) and BBSRC (Grant No. BB/R013063/1). S.C. is funded by Medical Research Council UK grants (MR/M01360X/1, MR/R025576/1, and MR/R020973/1).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Crampin, Professor Mia
Authors: Gomez-Gonzalez, P. J., Andreu, N., Phelan, J. E., Florez de Sessions, P., Glynn, J. R., Crampin, A. C., Campino, S., Butcher, P. D., Hibberd, M. L., and Clark, T. G.
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health
Journal Name:Scientific Reports
Publisher:Nature Research
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Scientific Reports 9:5204
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record