## 3 Mycobacterium Ecology: The Underlying Resilience Biology
### Transcriptional Regulation  
The transcriptional network of mycobacteria is frequently referred to be composed by a large set of regulators, namely sigma (\(\sigma\)) factors that articulate within a distinctive transcriptome landscape and are re-orchestrated by a non-coding transcriptome. Among mycobacteria, the number of sigma protein genes in obligate pathogens is lower than in environmental opportunistic mycobacteria, as the panoply of conditions to which the latter have to adapt require the fine-tuning of gene expression and refined articulation within these sigma factors. In the obligate pathogen _M. tuberculosis_ genome, 13 \(\sigma\) subunits regulate transcription upon specific in vitro and in vivo conditions, reprogramming mycobacterial metabolism and physiology. The housekeeping regulation is assured by two \(\sigma\) factors (\(\sigma^{\text{A}}\) and \(\sigma^{\text{B}}\)), with the remaining 11 factors being recruited to respond to particular environmental conditions (\(\sigma^{\text{C-M}}\)) [40; 41]. Such factors belong to the \(\sigma^{\text{70}}\) family, whose members recognize two sequences in the promoter region of their target genes, the -10 element and the -35 element [40; 41]. For _M. tuberculosis_, the first element is recognized as being much more conserved than the latter. Several studies have been developed to infer the role of each factor, either by expression profiling or more recently by the construction of deletion mutants. In addition to its function as a housekeeping regulator, the \(\sigma^{\text{B}}\) subunit was indicated as a major stress response factor [40; 41]. The \(\sigma^{\text{B}}\), \(\sigma^{\text{F}}\), \(\sigma^{\text{G}}\), \(\sigma^{\text{I}}\), and \(\sigma^{\text{J}}\) were shown to be involved in stationary phase regulation [40; 41]. Starvation was shown to be regulated by \(\sigma^{\text{D}}\), \(\sigma^{\text{E}}\), and \(\sigma^{\text{F}}\), while \(\sigma^{\text{E}}\) was also found to be involved during pH stress [40; 41]. Growth under low-temperature reveals the involvement of \(\sigma^{\text{H}}\) and \(\sigma^{\text{I}}\), while under high-temperatures \(\sigma^{\text{H}}\), \(\sigma^{\text{E}}\), and \(\sigma^{\text{M}}\) play major roles in the regulation circuitry [40; 41]. The \(\sigma^{\text{C}}\), \(\sigma^{\text{E}}\), \(\sigma^{\text{H}}\), and \(\sigma^{\text{J}}\) were reported to be convoluted in regulation under oxidative stress [40; 41]. The existence of such a wide set of \(\sigma\) regulators enables a remarkable transcriptional adaptation to several environmental conditions. Comparativegenomics studies have been employed to understand regulation across NTM members. [PERSON] and coworkers (2005) predicted the existence of 26 \(\sigma\) factors in the genome of _M. smegmatis_, twice as much as that found in the _M. tuberculosis_ genome [42]. Although no orthologs of _sigC_, _sigI_, and _sigK_ were found, a significant enrichment of _sigH_ was uncovered and, to a lesser extent, of the _sigJ_ and _sigL_ subfamilies [42]. These paralogous members provide evidence of gene duplication and speciation in mycobacteria. Especially in the case of _sigH_, which is associated with oxidative and temperature stress, it may reflect the evolution of complex regulatory pathways developed in this saprophyte [42]. Similarly to _M. tuberculosis_, the roles of \(\sigma^{\text{A}}\) and \(\sigma^{\text{B}}\) housekeeping regulators in _M. smegmatis_ and _M. abscessus_ have been clarified, with evidence of co-transcription of housekeeping genes during exponential growth [43]. In _M. smegmatis_, _sigF_, a stationary phase regulator in _M. tuberculosis_, was also shown to be involved in heat shock, acidic pH, and oxidative stress responses [44]. In the fastidious _Mycobacterium avium_ subsp. _paratuberculosis_ (MAP), 19 putative \(\sigma\) factors have been identified across its genome [45], of which five are considered species-specific, one is homologous to _M. tuberculosis_', two are homologous to _M.