signature=204e83e83b6d97228c219d793c6cb411,Epigenetic regulation of the immune system in health and ...

Tissue Antigens ISSN0001-2815 R E V I E W A R T I C L E

Epigenetic regulation of the immune system in health

and disease

J.L.Fern′andez-Morera1,V.Calvanese2,S.Rodr′?guez-Rodero3,E.Men′endez-Torre1&M.F.Fraga2,3

1Endocrinology and Nutrition Service,Hospital Universitario Central de Asturias,Oviedo,Spain

2Department of Immunology and Oncology,Centro Nacional de Biotecnolog′?a/CNB-CSIC,Cantoblanco,Madrid,Spain

3Cancer Epigenetics Laboratory,Instituto Universitario de Oncolog′?a del Principado de Asturias(IUOPA),Universidad de Oviedo,Oviedo,Spain

Key words

acetylation;epigenetics;immune system; methylation

Correspondence

Mario F.Fraga

Department of Immunology and Oncology Centro Nacional de Biotecnolog′?a/CNB-CSIC Cantoblanco

Madrid E-28049

Spain

Tel:+3498519475

Fax:+34985106192

e-mail:mffraga@cnb.csic.es

doi:10.1111/j.1399-0039.2010.01587.x Abstract

Epigenetics comprises various mechanisms that mold chromatin structures and regulate gene expression with stability,thus de?ning cell identity and function and adapting cells to environmental changes.Alteration of these mechanisms contributes to the inception of various pathological conditions.Given the complexity of the immune system,one would predict that a higher-order,supragenetic regulation is indispensable for generation of its constituents and control of its functions.Here,we summarize various aspects of immune system physiology and pathology in which epi-genetic pathways have been implicated.Increasing knowledge in this?eld,together with the development of speci?c tools with which to manipulate epigenetic pathways, might form a basis for new strategies of immune function modulation,both to opti-mize immune therapies for infections or cancer and to control immune alterations in aging or autoimmunity.

Environmental pressure modulates gene expression in the immune system through epigenetic mechanisms

The immune system is a complex,integrated ensemble of organs,tissues,cells,and cell products;its ability to differ-entiate self from non-self enables it to protect the organism from potentially pathogenic agents or substances.Epigenetic regulatory mechanisms are a central element in immune sys-tem differentiation and function,allowing an appropriate gene expression pattern in immune cells(1–3).Pathogenic factors might be considered as an environmental pressure that induces these epigenetic changes(4).

The term‘epigenetics’has classically been used to explain phenotypic events that cannot be described by genetic mecha-nisms.Conrad Waddington(1905–1975)de?ned epigenetics as‘the branch of biology that studies the causal interactions between genes and their products,which bring the pheno-type into being’(5).An updated de?nition now considers epigenetic conditions to be those that affect gene expression without changing the nucleotide sequence,in a way that can involve mitotic,or,less frequently,meiotic inheritance(6), conferring a certain stability on epigenetic events through cell generations.In this sense,epigenetics would include all mech-anisms involved in deploying the genetic information for var-ious processes that affect a cell’s life,including development,differentiation,stress response,pathological conditions,and environmental adaptation(7–8).

From a broader point of view,an epigenetic event is the link between genotype and phenotype;this mechanism alters gene expression,permitting a cell to adapt to environmen-tal pressure.Although most of the cells in a multicellular organism share the same genetic information,an organism produces many different cell types during its development, each characterized by a typical gene expression pro?le and by speci?c functions.Consequently,cell differentiation might be considered as a largely epigenetic phenomenon.Current epigenetic studies focus mainly on covalent modi?cations of DNA(deoxyribonucleic acid)and histone proteins,and on the mechanisms through which they alter chromatin structure. Other gene regulation tools such as non-coding RNA are also included among epigenetic pathways(9–10).

DNA methylation consists of the covalent addition of a methyl group at the5-position of cytosines,modifying the surface of the double helix major groove where DNA-binding proteins usually dock.This normally occurs on a cytosine fol-lowed by a guanine(CpG dinucleotide)and generally involves transcriptional silencing.CpG dinucleotides are concentrated in regions called CpG islands,located preferentially in pro-moter or regulatory regions;most of these dinucleotides are nonetheless found in repetitive DNA elements(11).DNA