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Mycobacterial Pan-Genome Analysis Suggests Important Role of Plasmids in the Radiation of Type VII Secretion Systems.

ABSTRACT: In mycobacteria, various type VII secretion systems corresponding to different ESX (ESAT-6 secretory) types, are contributing to pathogenicity, iron acquisition, and/or conjugation. In addition to the known chromosomal ESX loci, the existence of plasmid-encoded ESX systems was recently reported. To investigate the potential role of ESX-encoding plasmids on mycobacterial evolution, we analyzed a large representative collection of mycobacterial genomes, including both chromosomal and plasmid-borne sequences. Data obtained for chromosomal ESX loci confirmed the previous five classical ESX types and identified a novel mycobacterial ESX-4-like type, termed ESX-4-bis. Moreover, analysis of the plasmid-encoded ESX loci showed extensive diversification, with at least seven new ESX profiles, identified. Three of them (ESX-P clusters 1-3) were found in multiple plasmids, while four corresponded to singletons. Our phylogenetic and gene-order-analyses revealed two main groups of ESX types: 1) ancestral types, including ESX-4 and ESX-4-like systems from mycobacterial and non-mycobacterial actinobacteria and 2) mycobacteria-specific ESX systems, including ESX-1-2-3-5 systems and the plasmid-encoded ESX types. Synteny analysis revealed that ESX-P systems are part of phylogenetic groups that derived from a common ancestor, which diversified and resulted in the different ESX types through extensive gene rearrangements. A converging body of evidence, derived from composition bias-, phylogenetic-, and synteny analyses points to a scenario in which ESX-encoding plasmids have been a major driving force for acquisition and diversification of type VII systems in mycobacteria, which likely played (and possibly still play) important roles in the adaptation to new environments and hosts during evolution of mycobacterial pathogenesis.

SUBMITTER: Dumas E

PROVIDER: S-EPMC4779608 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Mycobacterial Pan-Genome Analysis Suggests Important Role of Plasmids in the Radiation of Type VII Secretion Systems.

Dumas Emilie E Christina Boritsch Eva E Vandenbogaert Mathias M Rodríguez de la Vega Ricardo C RC Thiberge Jean-Michel JM Caro Valerie V Gaillard Jean-Louis JL Heym Beate B Girard-Misguich Fabienne F Brosch Roland R Sapriel Guillaume G

Genome biology and evolution 20160108 2

In mycobacteria, various type VII secretion systems corresponding to different ESX (ESAT-6 secretory) types, are contributing to pathogenicity, iron acquisition, and/or conjugation. In addition to the known chromosomal ESX loci, the existence of plasmid-encoded ESX systems was recently reported. To investigate the potential role of ESX-encoding plasmids on mycobacterial evolution, we analyzed a large representative collection of mycobacterial genomes, including both chromosomal and plasmid-borne ...[more]

PMID: 26748339

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Project description:BackgroundThe genome of Mycobacterium tuberculosis contains five copies of the ESX gene cluster, each encoding a dedicated protein secretion system. These ESX secretion systems have been defined as a novel Type VII secretion machinery, responsible for the secretion of proteins across the characteristic outer mycomembrane of the mycobacteria. Some of these secretion systems are involved in virulence and survival in M. tuberculosis; however they are also present in other non-pathogenic mycobacteria, and have been identified in some non-mycobacterial actinomycetes. Three components of the ESX gene cluster have also been found clustered in some gram positive monoderm organisms and are predicted to have preceded the ESX gene cluster.ResultsThis study used in silico and phylogenetic analyses to describe the evolution of the ESX gene cluster from the WXG-FtsK cluster of monoderm bacteria to the five ESX clusters present in M. tuberculosis and other slow-growing mycobacteria. The ancestral gene cluster, ESX-4, was identified in several nonmycomembrane producing actinobacteria as well as the mycomembrane-containing Corynebacteriales in which the ESX cluster began to evolve and diversify. A novel ESX gene cluster, ESX-4EVOL, was identified in some non-mycobacterial actinomycetes and M. abscessus subsp. bolletii. ESX-4EVOL contains all of the conserved components of the ESX gene cluster and appears to be a precursor of the mycobacterial ESX duplications. Between two and seven ESX gene clusters were identified in each mycobacterial species, with ESX-2 and ESX-5 specifically associated with the slow growers. The order of ESX duplication in the mycobacteria is redefined as ESX-4, ESX-3, ESX-1 and then ESX-2 and ESX-5. Plasmid-encoded precursor ESX gene clusters were identified for each of the genomic ESX-3, -1, -2 and -5 gene clusters, suggesting a novel plasmid-mediated mechanism of ESX duplication and evolution.ConclusionsThe influence of the various ESX gene clusters on vital biological and virulence-related functions has clearly influenced the diversification and success of the various mycobacterial species, and their evolution from the non-pathogenic fast-growing saprophytic to the slow-growing pathogenic organisms.

Project description:BackgroundRole of TC2N in carcinogenesis has been largely unfathomed until recently when it was identified as a novel oncogene in lung cancer. Subsequently, a tumour suppressor role of TC2N was reported in breast cancer. It is therefore highly relevant to investigate TC2N molecular partners/mechanisms on a larger scale including a wider range of tumour types.MethodsWe investigated TC2N mRNA expression, its promoter methylation levels, effects of TC2N transcription on overall patient survival, somatic mutations in TC2N gene and correlation between TC2N mRNA expression and other cancer genes in pan-cancer by using data available from the Cancer Genome Atlas (TCGA) and the Genotype Tissue Expression (GTEx) databases.ResultsTC2N mRNA expression was differentially regulated in 9/33 TCGA tumour types. Of these 9 tumours, 5 tumour types (cholangiocarcinoma, ovarian-serous-cystadenocarcinoma, rectal-adenocarcinoma, stomach-adenocarcinoma and thymoma) had significantly higher TC2N mRNA expression while 4 (pheochromocytoma-and-paraganglioma, skin-cutaneous-melanoma, thyroid-carcinoma and uterine-carcinosarcoma) had significantly lower TC2N mRNA expression compared to matched and normal controls. TC2N promoter was hypermethylated in most cancers while hypomethylated in head-and-neck-squamous-cell-carcinoma and kidney-renal-clear-cell carcinoma. TC2N transcription was positively correlated with transcription of several other cancer genes including genes from Myc, cell-cycle, Nrf2, Wnt, PI3K, Hippo, Notch, TGFβ and RAS/RTK pathways. Poor prognosis was associated with higher TC2N mRNA levels in pancreatic-adenocarcinoma and brain-lower-grade-glioma and lower TC2N mRNA levels in kidney-renal-clear-cell-carcinoma, mesothelioma, sarcoma and skin-cutaneous melanoma. Functional protein partners of TC2N were identified as STX2, SMEK1, SMEK2, STXBP5, SCARA5, MMRN1, CATSPER2, CATSPERB, CLEC4M and STAB2. Many of these proteins are key players in carcinogenesis of various cancers. Highest pathogenic somatic mutation rates in TC2N were found in skin-cutaneous-melanoma, uterine-corpus-endometrial-carcinoma, colon-endocervical-adenocarcinoma, bladder-urothelial-carcinoma and breast-invasive-carcinoma.ConclusionOur findings unravel several un-explored avenues related to the role of TC2N in tumourigenesis of several cancers, suggesting TC2N as an important player and a potential candidate for tumour-therapy.

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Mycobacterial Pan-Genome Analysis Suggests Important Role of Plasmids in the Radiation of Type VII Secretion Systems.

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Mycobacterial Pan-Genome Analysis Suggests Important Role of Plasmids in the Radiation of Type VII Secretion Systems.

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