Identification and functional analysis of essential, conserved, housekeeping and duplicated genes

Arun, P. V. Parvati Sai; Miryala, Sravan Kumar; Chattopadhyay, Subhayan; Thiyyagura, Kranthi; Bawa, Payal; Bhattacharjee, Madhuchhanda; Yellaboina, Sailu

doi:10.1002/1873-3468.12192

Cited by 14 publications

(14 citation statements)

References 49 publications

(50 reference statements)

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“…In order to identify the higher order functions of Mtb genes expressed across different conditions and in intracellular environment, we carried out FOA and functional interpretation of regulons, operons and pathways as following 39 .…”

Section: Resultsmentioning

confidence: 99%

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System-wide coordinates of higher order functions in host-pathogen environment upon Mycobacterium tuberculosis infection

Arun

Miryala

Rana

et al. 2018

Sci Rep

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Molecular signatures and their interactions behind the successful establishment of infection of Mycobacterium tuberculosis (Mtb) inside macrophage are largely unknown. In this work, we present an inter-system scale atlas of the gene expression signatures, their interactions and higher order gene functions of macrophage-Mtb environment at the time of infection. We have carried out large-scale meta-analysis of previously published gene expression microarray studies andhave identified a ranked list of differentially expressed genes and their higher order functions in intracellular Mtb as well as the infected macrophage. Comparative analysis of gene expression signatures of intracellular Mtb with the in vitro dormant Mtb at different hypoxic and oxidative stress conditions led to the identification of the large number of Mtb functional groups, namely operons, regulons and pathways that were common and unique to the intracellular environment and dormancy state. Some of the functions that are specific to intracellular Mtb are cholesterol degradation and biosynthesis of immunomodulatory phenolic compounds. The molecular signatures we have identified to be involved in adaptation to different stress conditions in macrophage environment may be critical for designing therapeutic interventions against tuberculosis. And, our approach may be broadly applicable for investigating other host-pathogen interactions.

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Section: Resultsmentioning

confidence: 99%

“…Functional over-representation analysis (FOA) was carried out using our previously described method 39 . For each gene in a gene group, we have converted p-value of differential expression into Z-score using, inverse normal Cumulative Distribution Function (CDF).…”

Section: Methodsmentioning

confidence: 99%

System-wide coordinates of higher order functions in host-pathogen environment upon Mycobacterium tuberculosis infection

Arun

Miryala

Rana

et al. 2018

Sci Rep

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“…To calibrate the gene group (containing n genes) FOA scores against the background distribution, we randomly sampled the n number of logFC values and calculated the random FOA score. We repeated this process over 100 000 times, mean and standard deviation of the sampling distribution was used for correction of the original score …”

Section: Methodsmentioning

confidence: 99%

“…We repeated this process over 100 000 times, mean and standard deviation of the sampling distribution was used for correction of the original score. 11,12 2.4 | Data collection, network construction, and network analysis VG and antibiotic resistant genes (ARG) for the pathogenic Mtb H37Rv are curated from PATRIC database. 13 The interacting partners for VG and ARG were extracted from the STRING database.…”

Section: Foa Of Gene Groupsmentioning

confidence: 99%

Impact of bedaquiline and capreomycin on the gene expression patterns of multidrug‐resistant Mycobacterium tuberculosis H37Rv strain and understanding the molecular mechanism of antibiotic resistance

Miryala

Anbarasu

Ramaiah

2019

J of Cellular Biochemistry

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The emergence of multidrug resistance (MDR), extensively drug‐resistant, and total drug‐resistant Mycobacterium tuberculosis (Mtb) strains have hampered the treatment of tuberculosis (TB). Capreomycin and Bedaquiline are currently used for MDR‐TB treatment. To understand the impact of these antibiotics on Mtb genes, we have curated the gene expression data where the Mtb cultures were exposed to the Bedaquiline and Capreomycin. Based on the P value cut off (<0.05) and logFC (<−0.5 and >+0.5) values, we have selected the top differentially expressed genes during the antibiotic exposures. We have observed that the top differentially expressed Mtb genes were related to universal stress genes, two‐component regulatory systems, and drug efflux pumps. We have curated the Mtb gene datasets and carried out the functional over‐representation analysis using the individual gene expression values. We further, constructed the gene interaction networks of antibiotic resistance genes and virulence genes of Mtb to understand the impact of the antibiotics at the molecular level and thus to understand the antimicrobial resistance and virulence patterns. Our study elucidates the impact of antibiotics on the Mtb genes at the molecular level and the positively enriched pathways, operons, and regulons data are helpful in understanding the resistance patterns in Mtb. The upregulated genes during the exposure of Bedaquiline and Capreomycin can be considered as potent drug targets for the development of new anti‐TB drugs.

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“…Onto-Tools 1 Pathway Express was used to map differentially expressed genes, and Gene Spring 12.6.1 software (Agilent Technologies, Santa Clara, CA, USA) was used to prepare corresponding heat map. Pathways that were up/downregulated during TNF induction and/or CIAP-KO were identified using the previously developed method on Gene-Set enrichment analysis ( 16 ). Genessets for mouse were downloaded from Bader lab.…”

Section: Methodsmentioning

confidence: 99%

Inhibitors of Apoptosis Protein Antagonists (Smac Mimetic Compounds) Control Polarization of Macrophages during Microbial Challenge and Sterile Inflammatory Responses

et al. 2018

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Apoptosis is a physiological cell death process essential for development, tissue homeostasis, and for immune defense of multicellular animals. Inhibitors of apoptosis proteins (IAPs) regulate apoptosis in response to various cellular assaults. Using both genetic and pharmacological approaches we demonstrate here that the IAPs not only support opportunistic survival of intracellular human pathogens like Chlamydia pneumoniae but also control plasticity of iNOS+ M1 macrophage during the course of infection and render them refractory for immune stimulation. Treatment of Th1 primed macrophages with birinapant (IAP-specific antagonist) inhibited NO generation and relevant proteins involved in innate immune signaling. Accordingly, birinapant promoted hypoxia, angiogenesis, and tumor-induced M2 polarization of iNOS+ M1 macrophages. Interestingly, birinapant-driven changes in immune signaling were accompanied with changes in the expression of various proteins involved in the metabolism, and thus revealing the new role of IAPs in immune metabolic reprogramming in committed macrophages. Taken together, our study reveals the significance of IAP targeting approaches (Smac mimetic compounds) for the management of infectious and inflammatory diseases relying on macrophage plasticity.

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Identification and functional analysis of essential, conserved, housekeeping and duplicated genes

Cited by 14 publications

References 49 publications

System-wide coordinates of higher order functions in host-pathogen environment upon Mycobacterium tuberculosis infection

System-wide coordinates of higher order functions in host-pathogen environment upon Mycobacterium tuberculosis infection

Impact of bedaquiline and capreomycin on the gene expression patterns of multidrug‐resistant Mycobacterium tuberculosis H37Rv strain and understanding the molecular mechanism of antibiotic resistance

Inhibitors of Apoptosis Protein Antagonists (Smac Mimetic Compounds) Control Polarization of Macrophages during Microbial Challenge and Sterile Inflammatory Responses

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