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      A Network of Paralogous Stress Response Transcription Factors in the Human Pathogen Candida glabrata

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          Abstract

          The yeast Candida glabrata has become the second cause of systemic candidemia in humans. However, relatively few genome-wide studies have been conducted in this organism and our knowledge of its transcriptional regulatory network is quite limited. In the present work, we combined genome-wide chromatin immunoprecipitation (ChIP-seq), transcriptome analyses, and DNA binding motif predictions to describe the regulatory interactions of the seven Yap (Yeast AP1) transcription factors of C. glabrata. We described a transcriptional network containing 255 regulatory interactions and 309 potential target genes. We predicted with high confidence the preferred DNA binding sites for 5 of the 7 CgYaps and showed a strong conservation of the Yap DNA binding properties between S. cerevisiae and C. glabrata. We provided reliable functional annotation for 3 of the 7 Yaps and identified for Yap1 and Yap5 a core regulon which is conserved in S. cerevisiae, C. glabrata, and C. albicans. We uncovered new roles for CgYap7 in the regulation of iron-sulfur cluster biogenesis, for CgYap1 in the regulation of heme biosynthesis and for CgYap5 in the repression of GRX4 in response to iron starvation. These transcription factors define an interconnected transcriptional network at the cross-roads between redox homeostasis, oxygen consumption, and iron metabolism.

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          Most cited references91

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          Structure and evolution of transcriptional regulatory networks.

          The regulatory interactions between transcription factors and their target genes can be conceptualised as a directed graph. At a global level, these regulatory networks display a scale-free topology, indicating the presence of regulatory hubs. At a local level, substructures such as motifs and modules can be discerned in these networks. Despite the general organisational similarity of networks across the phylogenetic spectrum, there are interesting qualitative differences among the network components, such as the transcription factors. Although the DNA-binding domains of the transcription factors encoded by a given organism are drawn from a small set of ancient conserved superfamilies, their relative abundance often shows dramatic variation among different phylogenetic groups. Large portions of these networks appear to have evolved through extensive duplication of transcription factors and targets, often with inheritance of regulatory interactions from the ancestral gene. Interactions are conserved to varying degrees among genomes. Insights from the structure and evolution of these networks can be translated into predictions and used for engineering of the regulatory networks of different organisms.
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            Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins.

            Chromatin immunoprecipitation (ChIP) is the gold-standard technique for localizing nuclear proteins in the genome. We used ChIP, in combination with deep sequencing (Seq), to study the genome-wide distribution of the Silent information regulator (Sir) complex in Saccharomyces cerevisiae. We analyzed ChIP-Seq peaks of the Sir2, Sir3, and Sir4 silencing proteins and discovered 238 unexpected euchromatic loci that exhibited enrichment of all three. Surprisingly, published ChIP-Seq datasets for the Ste12 transcription factor and the centromeric Cse4 protein indicated that these proteins were also enriched in the same euchromatic regions with the high Sir protein levels. The 238 loci, termed "hyper-ChIPable", were in highly expressed regions with strong polymerase II and polymerase III enrichment signals, and the correlation between transcription level and ChIP enrichment was not limited to these 238 loci but extended genome-wide. The apparent enrichment of various proteins at hyper-ChIPable loci was not a consequence of artifacts associated with deep sequencing methods, as confirmed by ChIP-quantitative PCR. The localization of unrelated proteins, including the entire silencing complex, to the most highly transcribed genes was highly suggestive of a technical issue with the immunoprecipitations. ChIP-Seq on chromatin immunoprecipitated with a nuclear-localized GFP reproduced the above enrichment in an expression-dependent manner: induction of the GAL genes resulted in an increased ChIP signal of the GFP protein at these loci, with presumably no biological relevance. Whereas ChIP is a broadly valuable technique, some published conclusions based upon ChIP procedures may merit reevaluation in light of these findings.
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              An iron homeostasis regulatory circuit with reciprocal roles in Candida albicans commensalism and pathogenesis.

              The mammalian gastrointestinal tract and bloodstream are highly disparate biological niches that differ in concentrations of nutrients such as iron. However, some commensal-pathogenic microorganisms, such as the yeast Candida albicans, thrive in both environments. We report the evolution of a transcription circuit in C. albicans that controls iron uptake and determines its fitness in both niches. Our analysis of DNA-binding proteins that regulate iron uptake by this organism suggests the evolutionary intercalation of a transcriptional activator called Sef1 between two broadly conserved iron-responsive transcriptional repressors, Sfu1 and Hap43. Sef1 activates iron-uptake genes and promotes virulence in a mouse model of bloodstream infection, whereas Sfu1 represses iron-uptake genes and is dispensable for virulence but promotes gastrointestinal commensalism. Thus, C. albicans can alternate between genetic programs conferring resistance to iron depletion in the bloodstream versus iron toxicity in the gut, and this may represent a fundamental attribute of gastrointestinal commensal-pathogens. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                09 May 2016
                2016
                : 7
                : 645
                Affiliations
                [1] 1Laboratoire de Biologie Computationnelle et Quantitative, Centre National de la Recherche Scientifique, Institut de Biologie Paris-Seine, UMR 7238, Sorbonne Universités, Université Pierre et Marie Curie Paris, France
                [2] 2École Normale Supérieure, Paris Sciences et Lettres Research University, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut de Biologie de l'École Normale Supérieure, Plateforme Génomique Paris, France
                [3] 3Centre National de la Recherche Scientifique, UMR 7592, Institut Jacques Monod, Université Paris Diderot, Sorbonne Paris Cité Paris, France
                [4] 4Évolution, Centre National de la Recherche Scientifique, Institut de Biologie Paris-Seine, UMR 7138, Sorbonne Universités, Université Pierre et Marie Curie Paris, France
                Author notes

                Edited by: Dominique Sanglard, University of Lausanne and University Hospital Center, Switzerland

                Reviewed by: Alejandro De Las Penas, Instituto Potosino de Investigacion Cientifica y Tecnologica, Mexico; Claudina Rodrigues-Pousadaj, Instituto de Tecnologia Química e Biológica Antonio Xavier, Portugal; Bernard Turcotte, McGill University, Canada

                *Correspondence: Gaelle Lelandais gaelle.lelandais@ 123456univ-paris-diderot.fr ;

                This article was submitted to Fungi and Their Interactions, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2016.00645
                4860858
                27242683
                444fed0d-803f-4628-9162-d0b950da10b6
                Copyright © 2016 Merhej, Thiebaut, Blugeon, Pouch, Ali Chaouche, Camadro, Le Crom, Lelandais and Devaux.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 February 2016
                : 18 April 2016
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 108, Pages: 16, Words: 12231
                Categories
                Microbiology
                Original Research

                Microbiology & Virology
                yeast,yap,chip-seq,transcriptome,regulatory networks,evolution
                Microbiology & Virology
                yeast, yap, chip-seq, transcriptome, regulatory networks, evolution

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