Browsing by Author "Hancioglu, Baris"

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    Non-monotonic Response to Monotonic Stimulus: Regulation of Glyoxylate Shunt Gene-Expression Dynamics inﾠ Mycobacterium tuberculosis
    (Public Library of Science, 2016) Ascensao, Joao A.; Datta, Pratik; Hancioglu, Baris; Sontag, Eduardo; Gennaro, Maria L.; Igoshin, Oleg A.; Bioengineering; Center for Theoretical Biological Physics
    Understanding how dynamical responses of biological networks are constrained by underlying network topology is one of the fundamental goals of systems biology. Here we employ monotone systems theory to formulate a theorem stating necessary conditions for non-monotonic time-response of a biochemical network to a monotonic stimulus. We apply this theorem to analyze the non-monotonic dynamics of the σB-regulated glyoxylate shunt gene expression in Mycobacterium tuberculosis cells exposed to hypoxia. We first demonstrate that the known network structure is inconsistent with observed dynamics. To resolve this inconsistency we employ the formulated theorem, modeling simulations and optimization along with follow-up dynamic experimental measurements. We show a requirement for post-translational modulation of σB activity in order to reconcile the network dynamics with its topology. The results of this analysis make testable experimental predictions and demonstrate wider applicability of the developed methodology to a wide class of biological systems.
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    The Psp system ofﾠMycobacterium tuberculosisﾠintegrates envelope stress-sensing and envelope-preserving functions
    (Wiley, 2015) Datta, Pratik; Ravi, Janani; Guerrini, Valentina; Chauhan, Rinki; Neiditch, Matthew B.; Shell, Scarlet S.; Fortune, Sarah M.; Hancioglu, Baris; Igoshin, Oleg; Gennaro, Maria Laura; Bioengineering
    The bacterial envelope integrates essential stress-sensing and adaptive functions; thus, envelope-preserving functions are important for survival. In Gram-negative bacteria, envelope integrity during stress is maintained by the multi-gene Psp response. Mycobacterium tuberculosis was thought to lack the Psp system since it encodes only pspA and no other psp ortholog. Intriguingly, pspA maps downstream from clgR, which encodes a transcription factor regulated by the MprAB-σE envelope-stress-signaling system. clgR inactivation lowered ATP concentration during stress and protonophore treatment-induced clgR-pspA expression, suggesting that these genes express Psp-like functions. We identified a four-gene set – clgR, pspA (rv2744c), rv2743c, rv2742c – that is regulated by clgR and in turn regulates ClgR activity. Regulatory and protein–protein interactions within the set and a requirement of the four genes for functions associated with envelope integrity and surface-stress tolerance indicate that a Psp-like system has evolved in mycobacteria. Among Actinobacteria, the four-gene module occurred only in tuberculous mycobacteria and was required for intramacrophage growth, suggesting links between its function and mycobacterial virulence. Additionally, the four-gene module was required for MprAB-σE stress-signaling activity. The positive feedback between envelope-stress-sensing and envelope-preserving functions allows sustained responses to multiple, envelope-perturbing signals during chronic infection, making the system uniquely suited to tuberculosis pathogenesis.