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Background One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized. Results Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles with impact on transforming processes during carcinogenesis. Conclusions We develop an extensive catalogue of human DNA methylomes at base resolution to better understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes. ; The research leading to these results received funding from: the European Research Council (ERC), grant EPINORC, under agreement number 268626; MICINN Projects–SAF2011-22803 and BFU2011-28549; Ministerio de Economía y Competitividad (MINECO), co-financed by the European Development Regional Fund, 'A way to achieve Europe' ERDF, under grant number SAF2014-55000-R; the Cellex Foundation; AGAUR Catalan Government Project #2009SGR1315; the Institute of Health Carlos III (ISCIII), under the Spanish Cancer Research Network (RTICC) number RD12/0036/0039, the Integrated Project of Excellence number PIE13/00022 (ONCOPROFILE) and the research grant PI11/00321; the Sandra Ibarra Foundation, under IV ghd Grants for breast cancer research; the Olga Torres Foundation; the European Community's Seventh Framework Programme (FP7/2007-2013), grant HEALTH-F5-2011-282510 – BLUEPRINT, and the Health and Science Departments of the Generalitat de Catalunya. H.H. is a Miguel Servet (CP14/00229) researcher funded by the Spanish Institute of Health Carlos III (ISCIII). D.T. and M.E. are ICREA Research Professors. ; Peer Reviewed ; Postprint (author's final draft)

Background One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized. Results Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles with impact on transforming processes during carcinogenesis. Conclusions We develop an extensive catalogue of human DNA methylomes at base resolution to better understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes. ; The research leading to these results received funding from: the European Research Council (ERC), grant EPINORC, under agreement number 268626; MICINN Projects–SAF2011-22803 and BFU2011-28549; Ministerio de Economía y Competitividad (MINECO), co-financed by the European Development Regional Fund, 'A way to achieve Europe' ERDF, under grant number SAF2014-55000-R; the Cellex Foundation; AGAUR Catalan Government Project #2009SGR1315; the Institute of Health Carlos III (ISCIII), under the Spanish Cancer Research Network (RTICC) number RD12/0036/0039, the Integrated Project of Excellence number PIE13/00022 (ONCOPROFILE) and the research grant PI11/00321; the Sandra Ibarra Foundation, under IV ghd Grants for breast cancer research; the Olga Torres Foundation; the European Community's Seventh Framework Programme (FP7/2007-2013), grant HEALTH-F5-2011-282510 – BLUEPRINT, and the Health and Science Departments of the Generalitat de Catalunya. H.H. is a Miguel Servet (CP14/00229) researcher funded by the Spanish Institute of Health Carlos III (ISCIII). D.T. and M.E. are ICREA Research Professors. ; Peer Reviewed ; Postprint (author's final draft)

AbstractSuper-enhancer-associated long non-coding RNAs (SE-lncRNAs) are a specific set of lncRNAs transcribed from super-enhancer (SE) genomic regions. Recent studies have revealed that SE-lncRNAs play essential roles in tumorigenesis through the regulation of oncogenes. The objective of this study was to elucidate the expression profile of SE-lncRNAs with concurrent assessment of associated mRNAs in leiomyomas and paired myometrium. Arraystar SE-lncRNAs arrays were used to systematically profile the differentially expressed SE-lncRNAs along with the corresponding SE-regulated protein coding genes in eight leiomyomas and paired myometrium. The analysis indicated 7680 SE-lncRNAs were expressed, of which 721 SE-lncRNAs were overexpressed, while 247 SE-lncRNAs were underexpressed by 1.5-fold or greater in leiomyoma. Thirteen novel SE-lncRNAs and their corresponding protein coding genes were selected, and their expression was confirmed in eighty-one paired leiomyoma tissues by quantitative real-time PCR. The thirteen pairs of SE-lncRNAs and their corresponding protein coding genes included RP11-353N14.2/CBX4, SOCS2-AS1/SOCS2, RP1-170O19.14/HOXA11, CASC15/PRL, EGFLAM-AS1/EGFLAM, RP11-225H22/NEURL1, RP5-1086K13.1/CD58, AC092839.3/SPTBN1, RP11-69I8.3/CTGF, TM4SF1-AS1/TM4SF1, RP11-373D23/FOSL2, RP11-399K21.11/COMTD1, and CTB-113P19.1/SPARC. Among these SE-lncRNAs, the expression of SOCS2-AS1/SOCS2, RP11-353N14.2/CBX4, RP1-170O19.14/HOXA11, and RP11-225H22/NEURL1 was significantly higher in African Americans as compared with Caucasians. The expression of RP11-353N14.2/CBX4, SOCS2-AS1/SOCS2, CASC15/PRL, and CTB-113P19.1/SPARC was significantly higher in tumors with MED12-mutation-positive as compared with MED12-mutation-negative tumors. Collectively, our results indicate that the differential expression of SE in leiomyomas is another mechanism contributing to dysregulation of protein coding genes in leiomyomas and that race and MED12 mutation can influence the expression of a select group of SE.

Linking non-coding genetic variants associated with the risk of diseases or disease relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type matched epigenomic data and promoter long-range interactions. We identified potential regulatory functions for 423 of 565 (75%) non-coding platelet variants and highlighted, including ex vivo and genome editing proof of principle validation, the role of associated variants in super enhancers in controlling archetypical platelet functions. ; The work was funded by a grant from the European Commission 7th Framework Program (FP7/2007-2013, grant 282510, BLUEPRINT). F.A.C. is a Medical Research Council (MRC) clinical fellow (MR/K024043/1); K.D. is funded by NHS Health Education England; M.F. is supported by the British Heart Foundation (BHF) Cambridge Centre of Excellence (RE/13/6/30180); research in the W.H.O. laboratory is also supported by grants from Bristol Myers-Squibb, BHF, European Commission, MRC, NIHR (W.H.O. is NIHR Senior Investigator) and NHS Blood and Transplant (NHSBT). RP is supported by the European Union's Horizon 2020 research and innovation program under grant agreement No. 692041 (TrainMALTA, H2020-TWINN-2015). L.V. is funded by the ERC grant Relieve IMDs (ERC-2011-StG). P.M. and A-S.L. are funded by the NIHR Cambridge Biomedical Research Centre (BRC) hIPSCs core facility. B.M.J., P.Fr. and M.S. are supported by the MRC (MR/L007150/1) and Biotechnology and Biological Sciences Research Council (BB/J004480/1). K.F. is funded by FWO-Vlaanderen (G.0B17.13N) and BOF KULeuven (OT/14/098). Work at EMBL-EBI received additional support from the Wellcome Trust (WT095908) to P.Fl and from the European Molecular Biology Laboratory to L.C., M.K., P.Fl. and O.S. The MRC/BHF Cardiovascular Epidemiology receives core support from the MRC (G0800270), the BHF (SP/09/002), the NIHR and NIHR Cambridge BRC, as well as grants from the European Research Council (268834), the European Commission FP7 (HEALTH-F2-2012-279233), Merck and Pfizer. J.D. is a BHF Professor, European Research Council Senior Investigator, and NIHR Senior Investigator. The NIHR Blood and Transplant Research Unit in Donor Health and Genomics at the University of Cambridge is funded by NIHR and NHSBT.

THE AUTHOR ASSESSES THE IMPORTANCE OF THE IOWA CAUCUSES AND THE SUPER TUESDAY PRIMARIES IN PRESIDENTIAL ELECTIONS. CONVENTIONAL WISDOM MAKES THE IOWA CAUCUSES A MAJOR PREDICTOR OF SUCCESS IN GAINING BOTH THE DEMOCRATIC AND REPUBLICAN NOMINATIONS AND CLAIMS THAT SUPER TUESDAY GIVES AN ADVANTAGE TO CONSERVATIVE DEMOCRATIC CANDIDATES. BUT THE FACTS ARE OTHERWISE, AND THE MYTHS ABOUT THE IOWA CAUCUSES AND SUPER TUESDAY PRIMARIES HAVE BEEN CREATED BY JOURNALISTS.

Les images en annexe ont été retirées de la version diffusée. ; Le domaine des Arts et des Lettres est un domaine en constante évolution qui s'ancre dans son contemporain et en reflète souvent les pensées, les doutes, les fantasmes. Au fil du temps, les Lettres et Arts ont connu nombre de supports et de thèmes qui ont participé à leur donner une immense diversité. Mais paradoxalement, l'étude des Lettres dans le cadre universitaire montre une certaine timidité à l'idée d'étudier certaines formes plus originales, plus nouvelles ou plus populaires. C'est en partie ce constat qui a motivé le présent travail : pourquoi ne pourrait-on pas prendre comme objet de recherche l'univers du super-héros ? 2013 célèbre les soixante-quinze ans de l'apparition du super-héros avec la parution des premières aventures d'un dénommé "Superman". Et soixante-quinze ans plus tard, force est de constater que le super-héros a connu un succès bien plus grand que celui prédit par les éditeurs à l'époque. Véritable pilier de la culture occidentale, on retrouve aujourd'hui le super-héros partout dans notre société : en bande dessinée, au cinéma, dans les jeux vidéo ainsi que dans de nombreux produits dérivés et clins d'œil. Même les gens n'ayant aucun intérêt pour cet univers ont déjà entendu parler de Batman, Superman, Spiderman et autres de ces personnages hauts en couleurs. Mais malgré cette influence dans notre culture, on peut aussi constater que le monde des super-héros est très méconnu. En observant les gens, nous nous sommes rendu compte qu'un grand nombre d'entre eux pensaient encore que les super-héros et les bandes dessinées étaient réservés à un jeune public. Également, les films adaptés de ces bandes dessinées sont généralement perçus comme des divertissements. Le super-héros est encore aujourd'hui vu avec une certaine légèreté, comme un personnage populaire et amusant. Seuls les aficionados les plus fervents semblent garder à l'esprit que les super-héros offrent également tout un champ de réflexion morale ou politique. La présente étude prend pour objectif d'analyser le couple super-héros/super-vilains comme un double didactique et politique. L'idée étant que par l'association héros/vilains, la bande dessinée, comme le cinéma, ouvre la réflexion sur les concepts de Bien et de Mal, sur la notion de sacrifice, d'abnégation, d'idéalisme mais également pose la question des origines du mal, du danger de la puissance ou encore de la légitimité du justicier. Cette étude tend à analyser le couple héros/vilains comme à la fois illustration de rapports d'opposition et à la fois illustration de rapports de similitude. Pour présenter le double héros/vilains comme support didactique, nous avons voulu explorer quatre points. Le premier retrace l'Histoire du super-héros dans la bande dessinée comme dans d'autres médias, ses réussites, ses limites, ses détracteurs. Cette entrée en matière a pour objectif de montrer à quel point le monde du super-héros est ancré dans notre société et voir comment il a déjà pu être source de débats ou bannière politique. Le deuxième point aborde le couple héros/vilains sous un angle manichéen, soulignant les aspects positifs du super-héros et les aspects négatifs du super-vilain. Le but étant de montrer que par un système d'oppositions (de valeurs, d'aspect, d'identités.) ce couple permet la mise en relief de valeurs positives et de figures exemplaires. Une troisième partie tend à explorer les nuances de gris dans le double héros/vilain et à explorer la face cachée du super-héros. De par leur puissance supérieure à celle du commun des mortels, les super-héros ont souvent été décrits comme sources de dangers. De nombreux auteurs ont également soulevé la question de leur légitimité. D'autres ont cherché à voir s'ils n'étaient pas aussi dérangés que les adversaires qu'ils affrontaient. Enfin, cette partie pose également la question du héros comme origine indirecte du Mal, avec le fait que de nombreux vilains apparaissent dans leur seul but de combattre ces êtres supérieurs. Finalement, une quatrième partie explore le monde des super-héros aujourd'hui. En soixante-quinze ans, les super-héros ont connu de nombreuses redéfinitions, de nombreuses adaptations à leurs époques. Avec leur représentation massive au cinéma depuis les années 2000, les super-héros sont entrés dans une nouvelle ère et connaissent une nouvelle naissance. Nous avons pensé qu'il était intéressant de voir quelle était la vision portée sur le super-héros aujourd'hui et quel chemin il était en train de prendre, quel avatar il était sur le point d'incarner. Cette étude est poursuivie sur deux années de master. Le présent travail constitue la première moitié du mémoire et ne comprend donc que les deux premières parties évoquées ci-dessus. L'année 2013-2014 aura pour but de développer les deux dernières parties et ainsi de compléter la démarche initiée en M1.

The most striking campaign finance development since the Supreme Court's Citizens United decision has not been an upsurge in corporate or union spending as many commentators predicted. Instead, federal election campaigns have witnessed the emergence of a new campaign finance vehicle – the Super PAC – which relies primarily on extremely large individual contributions, not corporate or union money, but which threatens to upend the federal campaign finance regime in place since 1974. Super PACs can accept contributions in unlimited amounts and use them to engage in unlimited independent expenditures expressly supporting or opposing candidates. Non-existent before the spring of 2010, Super PACs were significant players in a number of 2010 Congressional elections and became major factors in the 2012 Republican presidential nominating contest. In many of the Republican primaries, Super PACs outspent the candidates. Nearly all the leading Super PACs in 2011-12 were closely identified with specific presidential contenders, and they became vehicles for wealthy donors who had given the legal maximum in contributions to a candidate's campaign to give much more to the Super PAC backing that candidate. As a result, Super PACs threaten to effectively eliminate limits on contributions to candidates. This article examines the Super PAC phenomenon. It compares and contrasts Super PACs with other campaign finance actors. It considers the judicial and Federal Election Commission decisions that authorized their existence and operations, and the impact of Citizens United – which is not directly responsible for Super PACs – in creating an atmosphere in which lower courts concluded that donations to independent spending committees cannot be limited. The article explores the preliminary data on Super PAC fundraising and spending and the evidence that they function as virtual, but legally far less constrained, alter egos for the candidates they support. As a result, the emergence of Super PACs may very well spell the beginning of the end of our nearly four-decade-old post-Watergate campaign finance regime.

The most striking campaign finance development since the Supreme Court's decision in Citizens United v. FEC in January 2010 has not been an upsurge in corporate and union spending, as might have been expected from a decision invalidating the decades-old laws barring such expenditures. Instead, federal election campaigns have been marked by the emergence of an entirely new campaign vehicle, which uses – but is not primarily dependent on – corporate or union funds, and which threatens to upend the federal campaign regulatory regime in place since 1974. The 2010 election cycle witnessed the birth of the "Super PAC" – a political action committee legally entitled to raise donations in unlimited amounts. Nonexistent and probably illegal before the spring of 2010, Super PACs spent an estimated $65 million on independent expenditures in 2010, and were significant players in more than a dozen Senate and House races. By early 2012, Super PACs were already major participants in the 2011-2012 election cycle, significantly outspending the candidates in the early Republican presidential nominating contests. Some Super PACs had spent millions of dollars on Senate general election contests that were more than ten months away. Although some Super PAC funds come from corporations and unions, the vast majority have been provided by wealthy individuals who, well before Citizens United, were permitted to spend unlimited sums independently, but were subject to a federal statutory limit of $5000 on the amounts they could give to the federal PACs that expressly support or oppose federal candidates. Citizens United did not address the statutory limits on individual donations to PACs. The Court's overruling of Austin v. Michigan Chamber of Commerce and the pertinent part of McConnell v. Federal FEC focused on the constitutional status of corporate campaign participation and the protection of independent spending, not on the rules governing contributions to political committees. The authorization of Super PACs followed directly from lower court decisions, including two that predated Citizens United and advisory opinions of the Federal Election Commission (FEC). But Citizens United – particularly the Supreme Court's flat assertion that independent expenditures, whatever their actual effect on the political process, raise no danger of corruption or the appearance of corruption within the meaning of Buckley v. Valeo – provided crucial doctrinal support for the legal actions that launched Super PACs and enabled them to flourish. The rise of Super PACs indicates that the real impact of Citizens United may be the re-validation of the unlimited use of private wealth in elections, not just spending by corporations and unions. This Article considers the emergence of Super PACs and their implications for the future of American campaign finance law. Part I explains what a Super PAC is and how it differs from other campaign finance vehicles. Part II analyzes the law of Super PACs, including the doctrinal tension out of which they emerged and the court and agency decisions authorizing their existence and operations. Part III examines the place of Super PACs in the campaign finance system, particularly their role in the 2010 congressional elections and their potential impact on the 2012 races based on fundraising and spending as of early 2012. In their brief life span, Super PACs have already begun to evolve from general ideological or partisan committees to vehicles for advancing or opposing the fortunes of specific candidates. This threatens to obliterate the significance of the limits on contributions to candidates that have been a centerpiece of federal campaign finance regulation since the post- Watergate reforms enacted in 1974. Part IV concludes by considering the implications of Super PACs for the future of American campaign finance law.

Cover -- Half Title -- Title -- Copyright -- Contents -- Introduction -- 1. The Assault of the Super PACs -- 2. Super PACs Weaken the US Political System -- 3. Have Faith in the American Voter -- 4. Corporations Aren't Persons -- 5. Corporations that Donate Money have the Right to Political Speech -- 6. Speech of Super PAC Donors Drowns Out the Speech of Average Americans -- 7. Super PACs may Further Constrain a Polarized Congress -- 8. Defending Citizens United -- 9. The Citizens United Decision that Supports Super PAC Spending is Flawed -- 10. Failure to Enforce Regulations Makes Super PACs More Powerful -- 11. A Constitutional Amendment is Necessary to Restore Democracy -- 12. Less Regulation of Campaigns will Reduce the Role of Money in Politics -- 13. Protect Democracy from Corporate Cash Tsunami -- Organizations to Contact -- Bibliography -- Index -- Back Cover

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