The role of epigenetic dysregulation in the epidemic of allergic disease

The epidemic of allergic disease in early life is one of the clearest indicators that the developing immune system is vulnerable to modern environmental changes. A range of environmental exposures epidemiologically associated with allergic disease have been shown to have effects on the foetal immune function in pregnancy, including microbial burden, dietary changes and environmental pollutants. Preliminary studies now suggest that these early effects on immune development may be mediated epigenetically through a variety of processes that collectively modify gene expression and allergic susceptibility and that these effects are potentially heritable across generations. It is also possible that rising rates of maternal allergy, a recognised direct risk factor for infant allergic disease, may be further amplifying the effects of environmental changes. Whilst effective prevention strategies are the ultimate goal in reversing the allergy epidemic, the specific environmental drivers, target genes, and intracellular pathways and mechanisms of early life immune programming are still unclear. It is hoped that identifying genes that are differentially regulated in association with subsequent allergic disease will assist in identifying causal pathways and upstream contributing environmental factors. In this way, epigenetic paradigms are likely to provide valuable insights into how the early environment can be modified to more favourably drive immune development and reverse the allergic epidemic

Inhibition of IFN-γ transcription by site-specific methylation during T helper cell development

Polarization of naïve CD4 T cells into T helper type 2 (T(H)2) cells is characterized by expression of IL-4 and silencing of IFN-γ. Here we show that during T(H)2 polarization, the DNA methyltransferase Dnmt3a is recruited to the IFN-γ promoter and correspondingly the promoter undergoes progressive de novo methylation. Notably, the CpG located at the −53 position becomes methylated rapidly and this methylation inhibits ATF2/c-Jun and CREB transcription factor binding in vitro. In vivo, the same factors bind to the unmethylated IFN-γ promoter in T helper type 1 (T(H)1) cells but not the methylated IFN-γ promoter in T(H)2 cells. Furthermore, methylation at the −53 CpG alone is sufficient to inhibit the IFN-γ promoter-driven reporter gene expression in a T(H)1 cell line. These findings suggest that rapid methylation of the evolutionarily conserved −53 CpG by Dnmt3a may suppress IFN-γ transcription in developing T(H)2 cells by directly inhibiting transcription factor binding

Stat4 limits DNA methyltransferase recruitment and DNA methylation of the IL-18Rα gene during Th1 differentiation

Stat4 is required for Th1 development, although how a transiently activated factor generates heritable patterns of gene expression is still unclear. We examined the regulation of IL-18Rα expression to define a mechanism for Stat4-dependent genetic programming of a Th1-associated gene. Although Stat4 binds the Il18r1 promoter following IL-12 stimulation and transiently increases acetylated histones H3 and H4, patterns of histone acetylation alone in Th1 cells may not be sufficient to explain cell-type-specific patterns of gene expression. The level of DNA methylation and recruitment of Dnmt3a to Il18r1 inversely correlate with IL-18Rα expression, and blocking DNA methylation increases IL-18Rα expression. Moreover, there was decreased Il18r1–Dnmt3a association and DNA methylation following transient trichostatin A-induced histone hyperacetylation in Stat4−/−Th1 cultures. Increased association of Dnmt3a and the Dnmt3a cofactor Dnmt3L with the promoters of several Stat4-dependent genes was found in Stat4−/− Th1 cultures, providing a general mechanism for Stat4-dependent gene programming. These data support a mechanism wherein the transient hyperacetylation induced by Stat4 prevents the recruitment of DNA methyltransferases and the subsequent repression of the Il18r1 locus

DNA Methyltransferase Inhibitors: Development and Applications

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The Pierre Auger Observatory III: Other Astrophysical Observations

Astrophysical observations of ultra-high-energy cosmic rays with the Pierre Auger Observator

The Pierre Auger Observatory I: The Cosmic Ray Energy Spectrum and Related Measurements

Studies of the cosmic ray energy spectrum at the highest energies with the Pierre Auger Observator

The Pierre Auger Observatory scaler mode for the study of solar activity modulation of galactic cosmic rays

Since data-taking began in January 2004, the Pierre Auger Observatory has been recording the count rates of low energy secondary cosmic ray particles for the self-calibration of the ground detectors of its surface detector array. After correcting for atmospheric effects, modulations of galactic cosmic rays due to solar activity and transient events are observed. Temporal variations related with the activity of the heliosphere can be determined with high accuracy due to the high total count rates. In this study, the available data are presented together with an analysis focused on the observation of Forbush decreases, where a strong correlation with neutron monitor data is found.Comision Nacional de Energia Atomica, ArgentinaFundacion AntorchasGobierno De La Provincia de Mendoza, Municipalidad de Malargue, ArgentinaNDM HoldingsValle Las Lenas, ArgentinaAustralian Research Council (ARC)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Financiadora de Estudos e Projetos (FINEP)Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Ministério da Ciência, Tecnologia e Inovação do Brasil (MCTI)Academy of Sciences of the Czech Republic (AVCR) [AV0Z10100502] [AV0Z10100522] [GAAV KJB300100801] [KJB100100904] [MSMT-CR LA08016] [LC527] [1M06002] [MSM0021620859]Centre National de la Recherche Scientifique (CNRS), Centre de Calcul IN2P3/CNRSConseil Regional Ile-de-France, Departement Physique Nucleaire et Corpusculaire [PNC-IN2P3/CNRS]Departement Sciences de l`Univers (SDU-INSU/CNRS), FranceBundesministerium fur Bildung und Forschung (BMBF)Deutsche Forschungsgemeinschaft (DFG)Finanzministerium Baden-WurttembergHelmholtz-Gemeinschaft Deutscher Forschungszentren (HGF)Ministerium fur Wissenschaft und Forschung, Nordrhein-Westfalen, GermanyMinisterium fur Wissenschaft, Forschung und Kunst, Baden-Wurttemberg, GermanyIstituto Nazionale di Fisica Nucleare (INFN)Istituto Nazionale di Astrofisica (INAF)Ministero dell Istruzione, dell Universita e della Ricerca (MIUR), ItalyConsejo Nacional de Ciencia y Tecnologia (CONACYT), MexicoMinisterie van Onderwijs, Cultuur en Wetenschap, Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)Stichting voor Fundamenteel Onderzoek der Materie (FOM), NetherlandsMinistry of Science and Higher Education, Poland [1 P03 D 014 30] [N N202 207238]Fundacao para a Ciencia e a Tecnologia (FCT), PortugalMinistry for Higher Education, Science, and Technology, Slovenian Research Agency, SloveniaComunidad de Madrid, SpainConsejeria de Educacion de la Comunidad de Castilla La ManchaFondo Europeo de Desarrollo Regional (FEDER)Ministerio de Ciencia e Innovacion, Consolider-Ingenio, SpainGeneralitat ValencianaJunta de AndaluciaXunta de Galicia, SpainScience and Technology Facilities Council, United KingdomU.S. Department of Energy (DOE) [DE-AC02-07CH11359] [DE-FR02-04ER41300]National Science Foundation (NSF) [0450696]Grainger Foundation USAALFA-EC / HELENEuropean Union [MEIF-CT-2005-025057] [PIEF-GA-2008-220240]United Nations Educational, Scientific and Cultural Organization (UNESCO

The Pierre Auger Observatory III: Other Astrophysical Observations

Astrophysical observations of ultra-high-energy cosmic rays with the Pierre Auger Observator