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© CSIC, During the last few decades, the genomes from hundreds of different living organisms have been fully sequenced. Decoding this vast amount of genetic information promises to unlock the molecular secrets of life in our planet as well as the molecular basis of human disease. However, this is far from trivial since in many species the protein-coding sequences (i.e. genes) only account for a small fraction of their genome, with the remaining non-coding sequences potentially playing regulatory functions. Moreover, within multicellular organisms, the genome is uniquely used in each cell type by introducing epigenetic modifications and/or adopting particular 3D conformations that can affect gene activity and expression without changing the underlying DNA sequences. Despite this complexity, recent advances in various -omics and genome editing technologies have dramatically improved our current understanding of genome function. Therefore, we are now in a unique position to sequence, analyze and modify genomes, and, thus, to improve not only our quality of life but also that of our planet.

DNA methylation is a biochemical process that modifies gene expression without changing the underlying DNA sequence, and this represents the molecular basis for imprinting and epigenetics. Recent reports have revealed alterations in DNA methylation profiles in the placenta of babies born from assisted reproductive technologies (ART). This supports several previous observations that suggested an increase in the prevalence of imprinting diseases following ART treatment, and also fits our observations regarding the metabolism and requirements of early human embryos. Human embryo culture media (HECM) are currently formulated according to requirements based on the mouse embryo model, and in fact need to pass the Mouse Embryo Assay test in order to be accepted by the relevant authorities, despite the fact that physiological (especially the time necessary to reach genomic activation) and biochemical requirements of mouse and human embryos are quite different. This commentary aims to explain some of the discrepancies, and emphasize why human embryo metabolism tells us that the composition of HECM, as well as the role of the MEA as a unique model, should be re-evaluated.

Paper-bagging treatment can transform non-transcribed MdMYB1 - 2 and MdMYB1 - 3 alleles into transcribed alleles through epigenetic regulations, resulting in the red pigmentation of a normally non-red apple cultivar 'Mutsu.' Anthocyanin biosynthesis in apples is regulated by MdMYB1/A/10, an R2R3-Type MYB gene. 'Mutsu,' a triploid apple cultivar harboring non-transcribed MdMYB1-2 and MdMYB1-3 alleles, retains green skin color under field conditions. However, it can show red/pink pigmentation under natural or artificial ultraviolet-B (UV-B) light exposure after paper-bagging and bag removal treatment. In the present study, we found that in 'Mutsu,' paper bagging-induced red pigmentation was due to the activation of non-transcribed MdMYB1-2/-3 alleles, which triggered the expression of downstream anthocyanin biosynthesis genes in a UV-B-dependent manner. By monitoring the epigenetic changes during UV-B-induced pigmentation, no significant differences in DNA methylation and histone modifications in the 5' upstream region of MdMYB1-2/-3 were recorded between the UV-B-treated fruit skin (red) and the fruit skin treated only by white light (green). In contrast, bag treatment lowered the DNA methylation in this region of MdMYB1-2/-3 alleles. Similarly, higher levels of histone H3 acetylation and trimethylation of H3 tail at lysine 4, and lower level of trimethylation of H3 tail at lysine 27 were observed in the 5' upstream region of MdMYB1-2/-3 in the skin of the fruit immediately after bag removal. These results suggest that bagging treatment can induce epigenetic changes, facilitating the binding of trans factor(s) to MdMYB1-2/-3 alleles, resulting in the activation of these MYBs after bag removal.

Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under- or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in antidepressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF-α receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions.

This week’s papers address the involvement of TGF-β signaling in the differentiation of T H 17 cells, a checkpoint that restrains the antitumor and antivirus activities of natural killer cells, and a mechanism for erasing a parental epigenetic memory in plant embryos.

This week’s article is a review that highlights how epigenetic factors may make cells more or less susceptible to oncogenic transformation.

Despite progress in identifying molecular pathophysiological processes in schizophrenia, valid biomarkers are lacking for both the disease and treatment response.This comprehensive review summarises recent efforts to identify molecular mechanisms on the level of protein and gene expression and epigenetics, including DNA methylation, histone modifications and micro RNA expression. Furthermore, it summarises recent findings of alterations in lipid mediators and highlights inflammatory processes. The potential that this research will identify biomarkers of schizophrenia is discussed.Recent studies have not identified clear biomarkers for schizophrenia. Although several molecular pathways have emerged as potential candidates for future research, a complete understanding of these metabolic pathways is required to reveal better treatment modalities for this disabling condition.Large longitudinal cohort studies are essential that pair a thorough phenotypic and clinical evaluation for example with gene expression and proteome analysis in blood at multiple time points. This approach might identify biomarkers that allow patients to be stratified according to treatment response and ideally also allow treatment response to be predicted. Improved knowledge of molecular pathways and epigenetic mechanisms, including their potential association with environmental influences, will facilitate the discovery of biomarkers that could ultimately be effective tools in clinical practice.

X-chromosome inactivation is a fascinating epigenetic phenomenon that is initiated by expression of a noncoding (nc)RNA, XIST, and results in transcriptional silencing of 1 female X. The process requires a series of events that begins even before XIST expression, and culminates in an active and a silent X within the same nucleus. We will focus on the role that transgenic systems have served in the current understanding of the process of X-chromosome inactivation, both in the initial delineation of an active and inactive X, and in the function of the XIST RNA. X inactivation is strictly cis-limited; recent studies have revealed elements within the X-inactivation center, the region required for inactivation, that are critical for the initial regulation of Xist expression and chromosome pairing. It has been revealed that the X-inactivation center contains a remarkable compendium of cis-regulatory elements, ncRNAs, and trans-acting pairing regions. We review the functional componentry of the X-inactivation center and discuss experiments that helped to dissect the XIST/Xist RNA and its involvement in the establishment of facultative heterochromatin.

Although certain acquired nongenetic (i.e., epigenetic) traits are known to be heritable in plants, little is known currently about whether environmental parameters can induce adaptive epigenetic responses in plants and whether such effects can persist through generations. We used an experimental design based on classical genetics principles to assess whether plants respond to the environmental conditions of their ancestors in an adaptive epigenetic manner. An extensive examination of genetically identical Arabidopsis thaliana (L.) Heynh lines exposed to mild heat (30 °C) or cold (16 °C) treatments in the parental and F1generations revealed that the prior elevated temperature regime lead to a greater than fivefold improvement in fitness (seed production per individual) for plants exposed to heat in a later generation (F3). The heat-specific fitness improvements among F3plants were observed even though the heat-treated parental and F1generations were followed by a generation grown at a normal temperature (F2) and point towards a temperature-induced adaptive epigenetic phenomenon. No such adaptive responses were detected for cold-treated plants, indicating that there are distinctive biological processes inherent to these two temperature regimes. Overall, the data are consistent with the existence of an environmentally induced epigenetic and heritable adaptive response in plants.

Epigenetic control is required to maintain competency for the activation and suppression of genes during cell division. The association between regulatory proteins and target gene loci during mitosis is a parameter of the epigenetic control that sustains the transcriptional regulatory machinery that perpetuates gene-expression signatures in progeny cells. The mitotic retention of phenotypic regulatory factors with cell cycle, cell fate, and tissue-specific genes supports the coordinated control that governs the proliferation and differentiation of cell fate and lineage commitment.

La cromatina és una estructura nucleoproteica, dinàmica i jeràrquicament organitzada dins del nucli cel•Iular. La seva estructura, organització i funció està controlada al llarg del cicle cel.lular, per processos epigenètics que produeixen canvis heretables que no afecten la seqüència de DNA. Entre aquests canvis es troben la metilació del DNA, les modificacions postraduccionals de les histones i desplegament de la cromatina orquestrat pels complexes remodeladors i proteïnes estructurals. Les modificacions postraduccionals de les histones es donen principalment de forma dinàmica i regulada a l'extrem N-terminal, canviant la seva càrrega i funció. Entre les diferents modificacions descrites, l'acetilació i la metilació de les histones H3 i H4, semblen tenir una importància especial sobre l'estructura i estat de la cromatina. En particular, l'acetilació de la lisina 16 de la histona H4 (H4K16Ac) per se impedeix la formació d'estructures compactes de cromatina. D'aquesta manera, s'associa l'estat desacetilat d'aquest residu a zones d'heterocromatina i transcripcionalment inactives, mentre que la hiperacetilació d'H4K16 està estretament vinculada a zones eucromàtiques i transcripcionalmentactives. La dinàmica d'acetilació-desacetiIació d' H 4K 16 està controlada principalment per l'equilibri de les activitats acetiltransferasa de MOF i desacetilasa de Si rT1 i Si rT2. Per tant, aquests dos grups d'enzims són essencials per el control de l'expressió gènica i de l'arquitectura de la cromatina dins del nucli, regulant la transició entre l'estat transcripcionalment actiu i inactiu de la cromatina. MOF és crucial per el desenvolupament embrionari , I a reparació del DNA i la progressió del cicle cel .lular, i la seva pèrdua està associada a l'augment de les aberracions cromosòmiques, a l'aturada del cicle cel.lular en G2/M i a l'augment de la inestabilitat genòmica. SirT1 i Si rT2 pertanyen a la classe III de desacetilases d'histones (HDACs), conegudes com sirtuïnes, i són crucials per el manteniment de la integritat genòmica, l'adaptació a l'entorn i l'envelliment, entre altres funcions. No obstant, dels set membres de sirtuïnes presents a mamífers, només Si rT2 i en menor mesura SirT1, han estat vinculades amb el control del cicle cel.lular. Concretament, Si rT2, tot i ser principalment citoplasmàtica, és transportada al nucli durant I a transició G2/M , moment en el que a través de la desacetilació d'H4K16 permet la monometilació d'H4K20 per PR-SET7 (la monometiI transferasa d'H4K20), determinant els nivells d'H4K2Ome2,3 en la resta del cicle cel.lular. Com a conseqüència, SirT2 està implicat en processos estrictament associat a aquestes modificacions, com la compactació dels cromosomes metafàsics, Ia progressió a través de mitosi, la replicació i reparació del DNA o la formació de l'heterocromatina. Fins al moment el paper de Si rT2 en el control de I a progressió a través de la mitosi ha estat atribuït a la regulació de diferents substrats. En particular, el control d'H4K2Ome1 dependent de SirT2 ha estat relacionat amb l'activació del checkpoint de G2/M en resposta a estrès, tot i que els mecanismes involucrats en l'aturada del cicle cel.lular eren del tot desconeguts. En aquest treball hem volgut indagar sobre com Si rT2 regula la transició G2/M i la seva coordinació amb la maquinària regulatória del checkpoint. Les nostres dades semblen indicar que SirT2 condueix a l'activació del checkpoint de G2/M a través de la regulació d' H4K 1 6Ac, H4K2Ome1 i el control de I a transcripció de gens relacionats amb el cicle cel.lular. Es descriu per primera vegada, com SirT2 controla H4K16Ac a través de la regulació de l'activitat i de l'estabilitat proteica de MOF durant G2/M. Concretament, SirT2 desacetila MOF durant G2/M i en promou la sortida de la cromatina, la inactivació i degradació, afavorint l'estat desacetilat d'H4K16 i la monometilació d'H4K20. En concordança, hem vist que MOF controla negativament la presència de PR-SET7 a la cromatina, mantenint així uns nivells adequats d'H4K2Omel abans d'entrar a mitosi i evitant la condensació prematura dels cromosomes. El nostre estudi suggereix que la interconnexió entre SirT2 i MOF està directament implicada en el control epigenètic del cicle cel.lular, contribuint al manteniment de l'estabilitat genòmica., Chromatin is a dynamical structure hierarchically organized to fit inside the nucleus. The structure, organization and function of chromatin are tightly controlled throughout the cell cycle by different epigenetic mechanisms, including DNA methylation and histone modifications. The histone post-translational modifications occur mainly in their N-terminal tail, and give rise to changes in the charge and function of the protein. Among the different histone modifications, lysine acetylation (K) is one of the best characterized. Acetylation of lysine 16 of histone H4 is the most frequently acetylated residue in eukaryotes and is a key regulator of high orders of chromatin structure. Thus, the deacetylated state of this residue is associated with heterochromatic and transcriptional inactive regions, whereas the acetylated form is found in euchromatic and transcriptional active regions. The dynamics of this histone mark is mainly governed by the acetyltransferase MOF and the NAD±-dependent deacetylases SirT1 and SirT2, which makes both groups of enzymes essential for the regulation of the gene expression and the control of chromatin organization. MOF is crucial in embryogenesis, DNA repair and the cell cycle progression. In fact, loss of MOF has been shown to induce cell cycle arrest during G2/M transition, increased chromosomal aberrations and genome instability. SirT 1 and SirT2 belong to Class III of histone deacetylases (HDACs), commonly referred as sirtuins. They play a key role in stress response, and in particular in protecting genome integrity. Among the seven mammalian sirtuins (SirT1-7), only SirT2 and to a lesser extend SirT1, have been linked with cell cycle regulation. In particular, SirT2, which mainly localizes to the cytoplasm during most of the cell cycle, shuttles to the nucleus in G2/M transition, where deacetylates H4K16Ac driving, among other things, H4K2Omel deposition by the histone methyltransferase PR-SETT. The control of H4K2Omel deposition determines the levels of H4K2Ome2,3 in the next cell cycle, which links SirT2 to the regulation of DNA replication and repair, as well as heterochromatin formation. Work from our group and others have shown that SirT2 plays a role in the control of mitosis progression. In particular, SirT2 is required for the cell cycle arrest in the G2/M checkpoint during stress response, process that has been related to SirT2-dependent regulation of H4K2Omel. However, the mechanisms behind the cell cycle arrest are still undefined. In the present work we aimed to elucidate the function of SirT2 in G2/M transition and its coordination with the checkpoint regulatory machinery. Our results seem indicate that SirT2 drives the G2/M checkpoint activation through the regulation of H4K16Ac, H4K2Omel and the control of the expression of cell cycle related genes. We also describe for the first time, a complementary mechanism whereby SirT2 regulates the levels of H4K16Ac during mitosis. We observe that SirT2 not only deacetylates MOF during G2/M, suppressing its acetyltransferase activity, but also induces both chromatin eviction and degradation of MOF. This in turn, results in H4K16 hypoacetylation and subsequent monomethylation of H4K20. Additionally, we show that MOF inhibits PR-SETT chromatin localization, maintaining the appropriate levels of H4K2Omel before entering mitosis and avoiding premature chromosome condensation. Our study suggests that the crosstalk between MOF and SirT2 is directly involved in the epigenetic control of the cell cycle, contributing to the maintenance of genome stability.

[要旨] 哺乳動物の生殖細胞サイクルでは、受精直後の初期胚と始原生殖細胞(primordial germ cell、PGC)において分化能を獲得するために重要な核のリプログラミングが二度引き起こされる。核のリプログラミングはピストンやDNAのエピジェネティック修飾の変化を伴うクロマチンリモデリングに起因し、直接的な制御因子としてヒストンやDNAを標的としたメチル化やアセチル化酵素が数多く同定されている。また、受精直後の初期胚の雄性ゲノムやPGCのゲノムでは、5一メチルシトシン(5-methylcytosine、5mC)のレベルの低下が能動的に起こることが認められている。現在、能動的にDNAを脱メチル化する酵素は同定されていないものの、能動的DNA脱メチル化機構の解明に向けて新たな局面が最近見られた。例えば、ten-eleven translocation (TET) ファミリータンパク質は5mCを酸化して5-ヒドロキシメチルシトシン(5-hydroxymethylcytosine、5hmC)へ変換する機能を持つことや、activation-induced deaminase(AID)及びapolipoprotein B mRNA editing enzyme catalytic polypeptides (APOBEC) は5mCをチミンへ変換する機能を持つことが明らかになった。これらのタンパク質は、間接的にDNAの脱メチル化を制御することがマウス初期胚及びPGCにおいて明らかにされている。さらに、多能性を持つES細胞では、AIDやTETIはOct4(Pou5f1としても知られている)とNanogにおけるプロモーター領域のDNA脱メチル化に関与することが報告されている。こうした能動的DNA脱メチル化機構の解明は、多能性に関わる遺伝子の発現機構をより明確にし、再生医療の進歩に貢献する。そこで本稿では、マウス初期胚とPGCにおける能動的DNA脱メチル化制御について概説する。 [Abstract] Early embryos and primordial germ cells (PGCs) undergo extensive epigenetic reprogramming in mammals. In these cells, methyltransferases and acetyltransferases have been identified and their activities are involved in the epigenetic reprogramming by mediating the histone modifications and DNA methylation, except for DNA demethylase. Recent reports have indicated mechanisms of active DNA demethylation. One of mechanism are that Ten-eleven translocation 3 (Tet3), which is intensely expressed in oocytes and zygotes, regulates the active DNA demethylation by global conversion of 5-methylcytosine (5mC) to 5-hydroxymethlcytosine (5hmC). In addition, activation-induced deaminase (AID) and apolipoprotein B mRNA editing enzyme catalytic polypeptides (APOBEC) are involved in active DNA demethylation during PGCs development by converting 5mC to thymine. Furthermore, AID is required for induction of Oct4/Pou5f1 and Nanog expression in mouse embryonic stem cells (ESCs), and TET 1 has an important role in mouse ESCs through maintaining the expression of Nanog. Thus, clarifying the mechanisms of active DNA demethylation leads to understanding the reprogramming toward pluripotency and totipotency. Here, we will review mechanisms of active DNA demethylation during preimplantation embryos and PGC development., 本研究は近畿大学生物理工学部戦略的研究No.10-IV-7, 2011の助成を受けた。

The epigenome, which comprises chromatin, associated proteins, and the pattern of covalent modification of DNA by methylation, sets up and maintains gene expression programs. It was originally believed that DNA methylation was the dominant reaction in determining the chromatin structure. However, emerging data suggest that chromatin can affect DNA methylation in both directions, triggering either de novo DNA methylation or demethylation. These events are particularly important for the understanding of cellular transformation, which requires a coordinated change in gene expression profiles. While genetic alterations can explain some of the changes, the important role of epigenetic reprogramming is becoming more and more evident. Cancer cells exhibit a paradoxical coexistence of global loss of DNA methylation with regional hypermethylation.

This review addresses the mechanisms by which epigenetic variation modulates plant gene regulation and phenotype. In particular we explore the scope for harnessing such processes within the context of crop genetic improvement. We focus on the role of DNA methylation as an epigenetic mark that contributes to epiallelic diversity and modulation of gene regulation. We outline the prevalence and distribution of epigenetic marks in relation to eukaryote developmental processes, and in particular identify where this may be relevant to crop traits both in terms of specific developmental stages and in relation to physiological responses to environmental change. Recent whole genome surveys have identified specific characteristics of the distribution of DNA methylation within plant genomes. Together with greater understanding of the mode of action of different maintenance and de novo methyltransferases, this provides an opportunity to modulate DNA methylation status at specific loci as an intervention strategy in crop genetic improvement. We discuss alternative approaches that may be suitable for harnessing such induced epiallelic variation. Most of the discussion is associated with Brassica crops, which demonstrate considerable morphological plasticity, segmental chromosomal duplication, and polyploidy.

Neoplastic adrenocortical lesions are common in humans and several species of domestic animals. Although there are unanswered questions about the origin and evolution of adrenocortical neoplasms, analysis of human tumor specimens and animal models indicates that adrenocortical tumorigenesis involves both genetic and epigenetic alterations. Chromosomal changes accumulate during tumor progression, and aberrant telomere function is one of the key mechanisms underlying chromosome instability during this process. Epigenetic changes serve to expand the size of the uncommitted adrenal progenitor population, modulate their phenotypic plasticity (i.e., responsiveness to extracellular signals), and increase the likelihood of subsequent genetic alterations. Analyses of heritable and spontaneous types of human adrenocortical tumors documented alterations in either cell surface receptors or their downstream effectors that impact neoplastic transformation. Many of the mutations associated with benign human adrenocortical tumors result in dysregulated cyclic adenosine monophosphate signaling, whereas key factors and/or signaling pathways associated with adrenocortical carcinomas include dysregulated expression of the IGF2 gene cluster, activation of the Wnt/β-catenin pathway, and inactivation of the p53 tumor suppressor. A better understanding of the factors and signaling pathways involved in adrenal tumorigenesis is necessary to develop targeted pharmacologic and genetic therapies.

Environmental Health Perspectives (EHP) established the Paper of the Year in 2008 (Tilson 2008) as a way of highlighting high-quality articles published in the journal. The EHP Classic Paper of the Year is given to the most highly cited Research Article, Commentary, or Review Article over the preceding 60 months. We are proud to announce that the 2013 EHP Classic Paper of the Year is “Effects of Particulate Matter on Genomic DNA Methylation Content and iNOS Promoter Methylation” by Letizia Tarantini, Matteo Bonzini, Pietro Apostoli, Valeria Pegoraro, Valentina Bollati, Barbara Marinelli, Laura Cantone, Giovanna Rizzo, Lifang Hou, Joel Schwartz, Pier Alberto Bertazzi, and Andrea Baccarelli, published in the February 2009 issue of EHP. Tarantini et al. (2009) investigated molecular mechanisms underlying health effects of particulate matter exposures using biomarkers of DNA methylation that reflect reprogramming of gene expression. Their 2009 publication was one of the first to report application of epigenetic markers in an environmental or occupational health context. This research has had a significant influence on human environmental health research. The study by Tarantini et al. (2009) was one of the first studies to report evidence that DNA methylation may be altered in response to short-term exposures, and that it may reflect effects of usual levels of exposure over longer periods of time as well. This study also showed that easy-to-collect biospecimens, such as whole blood samples, and stored archival samples could be used to study effects of exposures on the epigenome. Novel laboratory and statistical approaches used in the study have since become routine in research on the epigenetic effects of environmental agents. EHP congratulates Tarantini and colleagues for their sustained contribution to the environmental health science literature. They should be recognized for their outstanding contribution to the rapidly evolving field of environmental epigenetics.

[cat] L’epigenètica fa referència als canvis heretables en l'expressió gènica que no són causats per alteracions en la seqüència d'ADN. La metilació de la citosina en el dinucleòtid CpG és una de les modificacions epigenètiques més importants en els éssers humans, i les alteracions en els patrons de metilació de l’ADN són una característica comuna de tots els càncers. La metilació de l'ADN té un paper crucial en la regulació de l'arquitectura de la cromatina, i per tant en el control de l'expressió gènica i l'estructura cromosòmica. Tot i que la metilació de l'ADN es troba principalment en regions riques en CpGs dins d'elements repetitius i la hipometilació global va ser la primera alteració de la metilació de l'ADN detectada en els tumors, hi ha un fort biaix en tots els estudis de metilació, que es limiten en bona part a l'estudi de la hipermetilació d’illes CpG. El concepte desfasat que considerava el elements repetitius com seqüències parasitàries fa anys que s’ha abandonat, no obstant la majoria dels estudis a escala genòmica els ha ignorat. Per aquesta raó, els avenços en la comprensió dels mecanismes epigenètics que regulen elements repetitius poden contribuir a dilucidar la seva participació específica en els processos biològics. La desmetilació d'elements repetitius es produeix en l'envelliment i en processos patològics com el càncer, i s'ha associat amb la reactivació gènica i la inestabilitat genòmica. Elements Alu (membres de la família SINE - short interspersed elements - ) són els retrotransposons més abundants del genoma humà amb més d'1 milió de còpies per genoma haploide, el 10% de tot el genoma. Curiosament els elements Alu no estan distribuïts a l'atzar dins del genoma humà i tendeixen a acumular-se en les regions riques en gens. Els elements Alu contenen fins a un 33% del nombre total de CpGs del genoma i estan altament metilats en la majoria dels teixits somàtics. No obstant, una fracció d’Alus és manté desmetilada en cèl•lules normals i aquesta proporció s'incrementa en cèl•lules canceroses. Els elements Alu desmetilats solen trobar-se en dominis de cromatina activa i juguen un paper en la regulació i l'estabilitat genòmica. La nostra hipòtesi és que els elements Alu integrats en la cromatina activa poden participar en múltiples processos cel•lulars, incloent funcions crucials del desenvolupament i d’identitat cel•lular. El principal objectiu d'aquesta tesi ha estat identificar elements Alu desmetilats associats a un estat de la cromatina activa i determinar el seu paper en la regulació de l'expressió gènica. Hem identificat un subgrup d'elements Alu amb perfils epigenètics distintius i propis d'estats funcionals actius. A més hem observat que alguns elements Alu poden presentar perfils epigenètics específics d'estats patològics (com el càncer) o fisiològics (segons el tipus de cel•lular), així com que els elements Alu desmetilats en el teixit normal tenen un alt grau de conservació epigenètica. D'altra banda, hem identificat i caracteritzat dues regions promotores corresponents als gens GLDC i DIEXF que contenen elements Alu (ZALU3 i Aj2c1, respectivament) i que presenten un patró epigenètic dinàmic durant el desenvolupament i el càncer. Aquests elements Alu presenten canvis epigenètics que delimiten la regió reguladora d'aquests gens, la qual cosa es tradueix en perfils transcripcionals i proteics associats a l'estat epigenètic de l'Alu., [eng] Epigenetics refers to heritable changes in gene expression that occur without alteration in DNA sequence. DNA methylation plays a crucial role in the regulation of chromatin architecture and in the control of gene expression. Even though DNA methylation is found mostly in repetitive elements and widespread hypomethylation was the first DNA methylation abnormality detected in tumors, there is a strong bias in methylation studies as most of them are restricted to CpG islands hypermethylation. For that reason, advances in understanding the epigenetic mechanisms that regulate repetitive elements may contribute to elucidate their specific participation in biological processes. Demethylation of repeat elements occurs in aging and pathological processes, as cancer, and has been associated with gene reactivation and genomic instability. Alu elements are the most abundant retrotransposon in the human genome, with more than 1 million copies. Interestingly, Alu elements tend to accumulate in gene rich regions. Alu elements contain up to 33% of the total number of CpG sites in the genome and are highly methylated in most somatic tissues. Strikingly, a small fraction of Alus remains unmethylated in normal cells and this proportion is increased in cancer cells. We hypothesize that Alu elements embedded in active chromatin are likely to participate in multiple cell processes, including crucial functions in development and cell identity. The main objective of this thesis has been to identify Alu elements with an active chromatin state and to determine their role in gene expression regulation. We have identified a subset of Alu elements with different epigenetic patterns characteristic of active functional states. We have observed that Alu elements have specific epigenetic profiles associated with pathological (cancer) or physiological (cell type) states and that the epigenetic particularity of Alus unmethylated in normal tissue is conserved at evolutional level. Moreover, we have identified and characterized two promoter regions corresponding to GLDC and DIEXF genes that include Alu elements (ZALU3 and Aj2c1, respectively) with a dynamic epigenetic pattern during development and cancer. These Alus show epigenetic changes that are consistent with the transcriptional and proteomic profiles of these genes and define the boundaries of the regulatory region.

This review discusses the relevance of oxidative damage to metal-induced toxicity and carcinogenesis. Presented are important facts and mechanistic concepts on the capacity of selected transition metals, mainly Ni, but also Cu, Co, Cr, and briefly several others, to generate active oxygen species and other reactive intermediates under physiological conditions. These metals are known to be toxic and/or carcinogenic contaminants of the occupational and general environments. Their redox activity may underlay the mechanism of mediation of oxidative damage to cell constituents. The presentation is focused on selected issues relative to genetic and epigenetic toxicity and illustrated with examples of metal-mediated oxidative damage to the principal components of chromatin, i.e., DNA, histones, and protamines.

Environmental Health Perspectives (EHP) established the Paper of the Year in 2008 (Tilson 2008) as a way of highlighting high-quality articles published in the journal. Until now, the Paper of the Year for any given year was selected on the basis of citations received over the preceding 60 months. Starting this year, this award will be known as the EHP Classic Paper of the Year. This award will be given to the most highly cited Research Article, Commentary, or Review Article over the preceding 60 months. A new award, the EHP Paper of the Year, will honor a Research Article published in the preceding year. Final selection of both awards will be subject to approval by the EHP Board of Associate Editors. The winner of the EHP Paper of the Year will be announced later in the calendar year. We are proud to announce that the 2011 EHP Classic Paper of the Year is “Maternal Genistein Alters Coat Color and Protects Avy Mouse Offspring from Obesity by Modifying the Fetal Epigenome” by Dana C. Dolinoy, Jennifer R. Weidman, Robert A. Waterland, and Randy L. Jirtle. This article was published in the April 2006 issue of EHP (Dolinoy et al. 2006) and has been cited more than 35 times per year since it was published. At the time the paper was written, it was increasingly recognized that exposure to nutritional, chemical, and behavioral factors could alter gene expression and affect health and disease not only by mutating promoter and coding regions of genes but also by modifying the epigenome. The epigenome comprises the heritable changes in gene expression that occur in the absence of changes to the DNA sequence itself, including DNA methylation and chromatin packaging. If the genome is compared to the hardware in a computer, the epigenome is the software that directs the computer’s operation. Dolinoy et al. (2006) argued that identifying epigenetic targets and defining how they are influenced by nutrition and the environment might lead to the development of innovative diagnostic, treatment, and prevention strategies that target the “epigenomic software” rather than the “genomic hardware.” Dolinoy et al. (2006) used the viable yellow agouti (Avy) mouse as an epigenetic biosensor to demonstrate that genistein, the major phytoestrogen in soy, increases DNA methylation of the Agouti gene, resulting in population-level decreased incidence of adult-onset obesity, diabetes, and cancer. At the inception of this study, epidemiological data suggested that increased dietary genistein plays a role in decreased incidence of cancer in Asians compared with Westerners. Thus, they hypothesized that early dietary exposures, including genistein, might be linked to adult health status via epigenetic mechanisms. These authors demonstrated that maternal dietary genistein supplementation of mice during gestation at levels comparable to humans consuming high soy diets shifted the coat color of heterozygous viable yellow agouti (Avy/a) offspring toward pseudoagouti. This phenotypic change was significantly associated with increased methylation of six cytosine–guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. A significant finding was that genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from adult-onset obesity. Dolinoy et al. (2006) provided the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome. They also established the framework for future studies by showing that both genistein and methyl donors, such as folic acid, betaine, and choline, counteract DNA hypomethylation caused by bisphenol A, an endocrine-active agent used to make polycarbonate plastic. Their results showed that simple dietary changes can protect against the deleterious effects of environmental toxicants on the fetal epigenome (Dolinoy et al. 2007). EHP congratulates Dolinoy and colleagues for their contribution to the environmental health science literature. In addition to demonstrating that single-nucleotide polymorphisms can affect environmentally responsive genes, they demonstrated that early nutritionally and environmentally induced epigenetic modifications may be an alternative mechanism underlying individual susceptibilities to environmental agents.

diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE), a comprehensive resource of human cancer models for basic and translational research that encompasses gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines spanning many tumor types. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity through systematic integration of the genomic and pharmacologic datasets. In addition to rediscovering molecular features known to predict response to several drugs, we uncovered novel potential biomarkers of sensitivity and resistance to both targeted agents and chemotherapy drugs. For instance, our analysis revealed new in vitro markers associated with sensitivity to MEK inhibitors in NRAS-mutant cell lines. Also, we found that response to topoisomerase 1 inhibitors seems to be predicted largely by expression of a single gene. Finally, we observed that tissue lineage is a key predictor for sensitivity to certain compounds, providing rationale for clinical trials of these drugs in particular cancer types. Together, our results indicate that large, annotated cell-line collections may help to identify biomarkers that allow the stratification of patients for appropriate drug treatment at the preclinical stage. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.