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Epigenetics and Bacterial Infections Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Epigenetics and Bacterial Infections He´le` ne Bierne1,2,3,Me´ lanie Hamon1,2,3, and Pascale Cossart1,2,3 1Institut Pasteur, Unite´ des Interactions Bacte´ries-Cellules, Paris F-75015, France 2Inserm, U604, Paris F-75015, France 3INRA, USC2020, Paris F-75015, France Correspondence: [email protected] Epigenetic mechanisms regulate expression of the genome to generate various cell types during development or orchestrate cellular responses to external stimuli. Recent studies highlight that bacteria can affect the chromatin structure and transcriptional program of host cells by influencing diverse epigenetic factors (i.e., histone modifications, DNA methyla- tion, chromatin-associated complexes, noncoding RNAs, and RNA splicing factors). In this article, we first review the molecular bases of the epigenetic language and then describe the current state of research regarding how bacteria can alter epigenetic marks and machiner- ies. Bacterial-induced epigenetic deregulations may affect host cell function either to promote host defense or to allow pathogen persistence. Thus, pathogenic bacteria can be considered as potential epimutagens able to reshape the epigenome. Their effects might generate specific, long-lasting imprints on host cells, leading to a memory of infection that influences immunity and might be at the origin of unexplained diseases. pon a microbial attack, host cells undergo cells, or manipulate their half-lives via posttrans- Umassive changes in their transcriptional lational modifications (Bhavsar et al. 2007; Ribet program, mobilizing genes involved in key pro- and Cossart 2010; Perrett et al. 2011). Some bac- cesses (e.g., immunity, cell death/survival, and teria, such as the phytopathogen Xanthomonas, adhesion/motility) to trigger an appropriate even produce transcriptional activatorsthat func- response (Jenner and Young 2005). It is thus tion as eukaryotic transcription factors (Kay et al. not surprising that successful pathogens have 2007). www.perspectivesinmedicine.org developed specific mechanisms to deregulate However, selective activation or silencing the expression levels and/or kinetics of these of specific genes not only depends on transcrip- defense genes. Host transcription factors are tion factors, but also on their cross talk with first obvious targets to reprogram the genome epigenetic modulators, which regulate DNA ac- and bacteria use diverse tricks to alter their func- cessibility by controlling the chromatin struc- tion. For instance, bacterial factors can hi- ture. Epigenetic modifications of chromatin jack cellular signaling pathways that activate during development and in response to dis- or sequester transcription factors (e.g., NF-kB, tinct environmental factors contribute to adult IRF/STATs, or AP-1) in the cytosol of targeted phenotypic variability and susceptibility to a Editors: Pascale Cossart and Stanley Maloy Additional Perspectives on Bacterial Pathogenesis available at www.perspectivesinmedicine.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a010272 Cite this article as Cold Spring Harb Perspect Med 2012;2:a010272 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press H. Bierne et al. number of diseases, including cancers and met- ATP-Dependent Remodeling of abolic and autoimmune disorders (van Vliet Nucleosomes et al. 2007; Liu et al. 2008; Wilson 2008; Portela Sequence-dependent physical properties of andEsteller2010).Thisarticleuncoversthemost DNA, thermal motion, and binding of tran- recent data highlighting that epigenetic changes scription factors to DNA influence nucleosome can also contribute to and/or result from bac- mobility. Yet,the movement of histone octamers terial infectious diseases. After an overview of relative to DNA is mainly catalyzed by ATP-de- the complex mechanisms governing chroma- pendent remodeling enzymes that use energy tin dynamics, we will describe how they may from ATP hydrolysis to move, destabilize, evict, contribute to host response to infection and/ or reassemble nucleosomes (Hota et al. 2011). or are hijacked by bacteria to impose a tran- These ATPases are encoded by 27 genes in scriptional program beneficial for infection. humans and are usually associated with several Only animal pathogenic bacteria will be ad- other proteins within multiprotein complexes, dressed here; for chromatin targeting by plant grouped into four families: SWI/SNF, ISWI, pathogenic bacteria, we refer to recent reviews CHD, INO80/SWR (all abbreviations are listed (Ma et al. 2011b; Rivas 2011; Bierne and Cossart in Table 1) (Gangaraju and Bartholomew 2007; 2012). Hargreaves and Crabtree 2011). These complex- es contribute either to activation or repression CHROMATIN REGULATION OF GENE of transcription or both, depending on their EXPRESSION AND THE EPIGENETIC interaction with histones and other chroma- MEMORY tin-binding proteins. In eukaryotic cells, DNA is packaged with his- tones into chromatin, allowing its confinement into the tight space of the nucleus. The state of Posttranslational Modifications of Histones and DNA Methylation: compaction of chromatin not only organizes The Epigenetic Code the genome but also plays a major role in nu- clear processes requiring access to DNA, i.e., Nucleosome stability is also deeply influenc- transcription, replication, recombination, and ed by changes occurring in the nucleosome DNA repair. The structure of chromatin has itself. The histone octamer can be modified by several levels of organization (Woodcock and exchange of histone variants and by a pletho- Dimitrov 2001). On the lowest level, the struc- ra of posttranslational modifications (PTMs), ture is based on repeating units, the nucleo- such as acetylation, methylation, phosphoryla- www.perspectivesinmedicine.org somes, which consist of octamers of histone tion, ubiquitylation, sumoylation, ADP ribosy- proteins (two copies of each of the core histones lation, and others, mainly in the histone tails H2A, H2B, H3, and H4) around which 147 that protrude from the nucleosome (Kouzarides base pairs of DNA is wound. Nucleosomes line 2007; Suganuma and Workman 2011), but also, up along the DNA in nucleosomal arrays and as shown more recently, in globular domains associate with linker histone H1 (or its iso- (Tropberger and Schneider 2011). DNA can forms), nonhistone proteins, and RNAs, form- also be modified by methylation of the 5 posi- ing higher-order chromatin structures, such as tion of the pyrimidine ring of cytosine (5mC), the loosely packaged and transcriptionally ac- mainly in the context of CpG dinucleotides in tive euchromatin, or the highly condensed and somatic mammalian cells (Klose and Bird 2006; transcriptionally silent heterochromatin. Chro- Chen and Riggs 2011). matin-remodeling and modifying mechanisms These covalent modifications of chromatin, function together to dynamically control the the “chromatin marks,” are added or removed state of chromatin compaction and open or by a wide range of enzymes termed as “writ- close regions of the genome for appropriate ers,” such as histone acetyltransferases (HATs), outcomes. methyltransferases (HMTs), and kinases, and 2 Cite this article as Cold Spring Harb Perspect Med 2012;2:a010272 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Bacterial Targeting of Chromatin Table 1. Abbreviations and acronyms Name Full name Function 5mC/5mU 5-Methylcytosine/5-methyluracyl Modified DNA base 5hmC/ 5-Hydroxymethylcytosine/50-hydroxymethyluracyl Modified DNA base 5hmU 5fC 5-Formylcytosine Modified DNA base 5caC 5-Carboxylcytosine Modified DNA base AID/ Activation-induced cytidine deaminase/apolipoprotein Nucleic acid mutator APOBEC B mRNA-editing enzyme catalytic polypeptide BER/NER Base excision repair /nucleotide excision repair DNA repair BAHD1 Bromo adjacent homology domain-containing 1 Chromatin-repressor complex subunit CHD3/4 Chromodomain-helicase-DNA-binding protein 3/4 Nucleosome remodeler (Mi-2a/Mi-2b) CIITA Class II, major histocompatibility complex, transactivator Transcription factor DNMT DNA methyltransferase DNA writer G9a Euchromatic histone-lysine N-methyltransferase 2 Histone writer (EHMT2) (EHMT2) H2AK119ub Histone H2A ubiquitylated at lysine 119 Modified histone H3K9me 2/3 Histone H3 di/trimethylated at lysine 9 Modified histone H3K27me3 Histone H3 trimethylated at lysine 27 Modified histone H3K9ac Histone H3 acetylated at lysine 9 Modified histone H3K14ac Histone H3 acetylated at lysine 14 Modified histone H3K23ac Histone H3 acetylated at lysine 23 Modified histone H3T3 Histone H3 phosphorylated at threonine 3 Modified histone H3K9ac Histone H3 acetylated at lysine 9 Modified histone H3S10p Histone H3 phosphorylated at serine 10 Modified histone H4K9me Histone H4 methylated at lysine 9 Modified histone HMT Histone methylatransferase Modified histone HDM Histone demethylase Histone writer HDAC Histone deacetylase Histone writer HMT Histone methyltransferase Histone writer HP1 Heterochromatin protein 1 Chromatin-silencing factor reader IFN-g Interferon g Cytokine INO80 INOsitol requiring protein 80 Nucleosome remodeler www.perspectivesinmedicine.org IKKa IkB kinase a Kinase ISG Interferon-stimulated gene Gene ISWI Imitation switch (ISWI) Nucleosome remodeler JNK c-Jun amino-terminal kinases
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