Differential genome organization revealed by comparative topological analysis of Mycobacterium tuberculosis strains H37Rv and H37Ra

TL;DR

This study reveals how the 3D genome structure of two tuberculosis-causing bacteria strains differs, potentially explaining why one is less virulent.

Contribution

The first comprehensive Hi-C-based analysis of genome topology in Mycobacterium tuberculosis strains H37Rv and H37Ra.

Findings

H37Ra has larger chromosome interaction domains (CIDs) compared to H37Rv.

CID boundaries in H37Rv are enriched with highly expressed genes and operons.

Differentially expressed PE/PPE genes are located near CID boundaries in H37Rv but not in H37Ra.

Abstract

Recent studies have shown that three-dimensional architecture of bacterial chromatin plays an important role in gene expression regulation. However, genome topological organization in Mycobacterium tuberculosis, the etiologic agent of tuberculosis, remains unknown. On the other hand, the exact mechanism of differential pathogenesis in the canonical strains of M. tuberculosis H37Rv and H37Ra remains poorly understood in terms of their raw sequences. In this context, a detailed contact map from a Hi-C experiment is a candidate for what bridges the gap. Here, we present the first comprehensive report on genome-wide contact maps between regions of H37Rv and H37Ra genomes. We tracked differences between the genome architectures of H37Rv and H37Ra, which could possibly explain the virulence attenuation in H37Ra. We confirm the existence of a differential organization between the two strains most significantly a higher chromosome interaction domain (CID) size in the attenuated H37Ra strain. CID boundaries are also found enriched with highly expressed genes and with higher operon density in H37Rv. Furthermore, most of the differentially expressed PE/PPE genes were present near the CID boundaries in H37Rv and not in H37Ra. We also found a systemic reorganization of CIDs in both virulent H37Rv and avirulent H37Ra strains after hypoxia induction. Collectively, our study proposes a differential genomic topological pattern between H37Rv and H37Ra, which could explain the virulence attenuation in H37Ra.

Genome organization studies using chromosome conformation capture techniques have proved to be useful in establishing a three-dimensional (3D) landscape of bacterial chromatin. The sequence-based studies failed to unveil the exact mechanism for virulence attenuation in one of the Mycobacterium tuberculosis strains H37Ra. Moreover, as of today, no study investigated the 3D structure of the M. tuberculosis genome and how 3D genome organization affects transcription in M. tuberculosis. We investigated the genome topology in virulent and attenuated strains of M. tuberculosis using Hi-C. Our study demonstrated that virulent and attenuated M. tuberculosis strains exhibit distinct topological features that correlate with higher gene expression of virulence genes in the virulent H37Rv strain.

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