Computationally inferring modes of transcriptional regulation in Mycobacterium abscessus

Mycobacterium abscessus subspecies abscessus is a highly drug resistant mycobacteria and the most common respiratory pathogen among the rapidly growing non-tuberculous mycobacteria. We report here the first multi-omics approach to characterize the primary transcriptome, coding potential and potential regulatory regions of the Mycobacterium abscessus genome utilizing RNA-seq, dRNA-seq, ribosome profiling and LC-MS proteomics. In addition, we attempt to address the genome’s contribution to the molecular systems that underlie Mycobacterium abscessus’ adaptation and persistence in the human host through an examination of Mycobacterium abscessus' transcriptional responses to a number of clinically relevant conditions. These include hypoxia, exposure to sub-inhibitory concentrations of antibiotics and growth in an artificial sputum designed to mimic the conditions within the cystic fibrosis lung. To computationally infer the gene regulatory network for Mycobacterium abscessus we propose a novel statistical computational modelling approach: BayesIan gene regulatory Networks inferreD via gene Expression and compaRative genomics (BINDER). In tandem with derived experimental expression data, the property of genomic conservation is exploited to probabilistically infer a gene regulatory network in Mycobacterium abscessus. In particular, inference on regulatory interactions is conducted by combining ‘primary data’ from RNA-seq experiments derived from Mycobacterium abscessus and ‘auxiliary’ ChIP-seq data from the related Mycobacterium tuberculosis. The inferred relationships provide insight to regulon groupings in Mycobacterium abscessus. We construct an inter-conditional snapshot of the transcriptional landscape in Mycobacterium abscessus across a range of stress-inducing conditions comprising exposure to antimicrobial compounds as well as nutrient starvation and iron depletion. The research herein provides valuable elucidation on the transcriptional means through which Mycobacterium abscessus persists in hostile environments and mediates virulence in the human host.