41. Vermeulen M, Eberl HC, Matarese F, Marks H, Denissov S, et al. (2010) Quantitative Interaction Proteomics and Genome-wide Profiling of Epigenetic Histone Marks and Their Readers. Cell 142: 967–980. 42. Di Lorenzo A, Bedford MT (2011) Histone arginine methylation. FEBS LETTERS 585: 2024–2031. 43. Bedford MT, Clarke SG (2009) Protein arginine methylation in mammals: who, what, and why. Mol Cell 33: 1–13. 44. Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, et al. (2004) Histone deimination antagonizes arginine methylation. Cell 118: 545–553. 45. Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, et al. (2004) Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306: 279–283. 46. Nakashima K, Hagiwara T, Yamada M (2002) Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes. J Biol Chem 277: 49562–49568. 47. Raijmakers R, Zendman AJ, Egberts WV, Vossenaar ER, Raats J, et al. (2007) Methylation of arginine residues interferes with citrullination by peptidylarginine deiminases in vitro. J Mol Biol 367: 1118–1129. 48. Migliori V, Phalke S, Bezzi M, Guccione E (2010) Arginine/lysine-methyl/ methyl switches: biochemical role of histone arginine methylation in transcrip- tional regulation. Epigenomics 2: 119–137. 49. Hagiwara T, Hidaka Y, Yamada M (2005) Deimination of histone H2A and H4 at arginine 3 in HL-60 granulocytes. Biochemistry 44: 5827–5834. 50. Li P, Yao H, Zhang Z, Li M, Luo Y, et al. (2008) Regulation of p53 target gene expression by peptidylarginine deiminase 4. Mol Cell Biol 28: 4745–4758. 51. Yao H, Li P, Venters BJ, Zheng S, Thompson PR, et al. (2008) Histone Arg modifications and p53 regulate the expression of OKL38, a mediator of apoptosis. J Biol Chem 283: 20060–20068. 52. Denis H, Deplus R, Putmans P, Yamada M, Metivier R, et al. (2009) Functional connection between deimination and deacetylation of histones. Mol Cell Biol 29: 4982–4993. 53. Zhang X, Gamble MJ, Stadler S, Cherrington BD, Causey CP, et al. (2011) Genome-Wide Analysis Reveals PADI4 Cooperates with Elk-1 to Activate c-Fos Expression in Breast Cancer Cells. PLoS Genet 7: e1002112. doi:10.1371/ journal.pgen.1002112 54. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, et al. (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34: 395–402. 55. Ikari K, Kuwahara M, Nakamura T, Momohara S, Hara M, et al. (2005) Association between PADI4 and rheumatoid arthritis: a replication study. Arthritis Rheum 52: 3054–3057. 56. Kang CP, Lee HS, Ju H, Cho H, Kang C, et al. (2006) A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis Rheum 54: 90–96. 57. Anzilotti C, Pratesi F, Tommasi C, Migliorini P (2009) Peptidylarginine deiminase 4 and citrullination in health and disease. Autoimmun Rev. 58. Mastronardi FG, Wood DD, Mei J, Raijmakers R, Tseveleki V, et al. (2006) Increased citrullination of histone H3 in multiple sclerosis brain and animal models of demyelination: a role for tumor necrosis factor-induced peptidylargi- nine deiminase 4 translocation. J Neurosci 26: 11387–11396. 59. Wang-Johanning F, Rycaj K, Plummer JB, Li M, Yin B, et al. (2012) Immunotherapeutic potential of anti-human endogenous retrovirus-k envelope protein antibodies in targeting breast tumors. Journal of the National Cancer Institute 104: 189–210. 60. Skundric DS, Cai J, Cruikshank WW, Gveric D (2006) Production of IL-16 correlates with CD4+ Th1 inflammation and phosphorylation of axonal cytoskeleton in multiple sclerosis lesions. J Neuroinflammation 3: 13. PADI4 Regulates HP1 Binding to Histone H3 in MS 61. Vaknin-Dembinsky A, Balashov K, Weiner HL (2006) IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol 176: 7768–7774. 62. Hung HC, Lin CY, Liao YF, Hsu PC, Tsay GJ, et al. (2007) The functional haplotype of peptidylarginine deiminase IV (S55G, A82V and A112G) associated with susceptibility to rheumatoid arthritis dominates apoptosis of acute T leukemia Jurkat cells. Apoptosis 12: 475–487. 63. Arita K, Shimizu T, Hashimoto H, Hidaka Y, Yamada M, et al. (2006) Structural basis for histone N-terminal recognition by human peptidylarginine deiminase 4. Proc Natl Acad Sci U S A 103: 5291–5296. 64. Muchardt C, Guilleme M, Seeler JS, Trouche D, Dejean A, et al. (2002) Coordinated methyl and RNA binding is required for heterochromatin localization of mammalian HP1alpha. EMBO Rep 3: 975–981. 65. Dong S, Zhang Z, Takahara H (2007) Estrogen-enhanced peptidylarginine deiminase type IV gene (PADI4) expression in MCF-7 cells is mediated by estrogen receptor-alpha-promoted transfactors activator protein-1, nuclear factor-Y, and Sp1. Mol Endocrinol 21: 1617–1629. 66. Luo Y, Arita K, Bhatia M, Knuckley B, Lee YH, et al. (2006) Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization. Biochemistry 45: 11727–11736. 67. de Parseval N, Casella J, Gressin L, Heidmann T (2001) Characterization of the three HERV-H proviruses with an open envelope reading frame encompassing the immunosuppressive domain and evolutionary history in primates. Virology 279: 558–569. 68. Mallet F, Bouton O, Prudhomme S, Cheynet V, Oriol G, et al. (2004) The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology. Proc Natl Acad Sci USA 101: 1731–1736. 69. Straub RH (2007) The complex role of estrogens in inflammation. Endocrine reviews 28: 521–574. 70. Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, et al. (2006) Sex ratio of multiple sclerosis in Canada: a longitudinal study. The Lancet Neurology 5: 932–936. 71. Conti L, De Palma R, Rolla S, Boselli D, Rodolico G, et al. (2012) Th17 Cells in Multiple Sclerosis Express Higher Levels of JAK2, Which Increases Their Surface Expression of IFN-cR2. Journal of immunology (Baltimore, Md: 1950) 188: 1011–1018. 72. Dawson MA, Bannister AJ, Gottgens B, Foster SD, Bartke T, et al. (2009) JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 461: 819–822. 73. Kim JK, Mastronardi FG, Wood DD, Lubman DM, Zand R, et al. (2003) Multiple sclerosis: an important role for post-translational modifications of myelin basic protein in pathogenesis. Molecular & cellular proteomics: MCP 2: 453–462. 74. Batsche´ E, Yaniv M, Muchardt C (2006) The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nat Struct Mol Biol 13: 22–29. 75. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, et al. (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13: 227–231. 76. Wilcoxon F (1945) Individual comparisons by ranking methods. Biometrics Bulletin 1: 80–83. 77. Stolarov J, Chang K, Reiner A, Rodgers L, Hannon GJ, et al. (2001) Design of a retroviral-mediated ecdysone-inducible system and its application to the expression profiling of the PTEN tumor suppressor. Proc Natl Acad Sci U S A 98: 13043–13048. 78. Shechter D, Dormann HL, Allis CD, Hake SB (2007) Extraction, purification and analysis of histones. Nat Protoc 2: 1445–1457. PLOS Genetics | www.plosgenetics.org 15 September 2012 | Volume 8 | Issue 9 | e1002934