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Perspective

Immune Disease-Associated Variants in Gene Enhancers Point to BET Epigenetic Mechanisms for Therapeutic Intervention

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Pages 573-584 | Received 17 Oct 2016, Accepted 21 Nov 2016, Published online: 07 Dec 2016

References

  • Hindorff LA , SethupathyP , JunkinsHAet al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits . Proc. Natl Acad. Sci. USA106 ( 23 ), 9362 – 9367 ( 2009 ).
  • Manolio TA . Genomewide association studies and assessment of the risk of disease . N. Engl. J. Med.363 ( 2 ), 166 – 176 ( 2010 ).
  • Nicolae DL , GamazonE , ZhangW , DuanS , DolanME , CoxNJ . Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS . PLoS Genet.6 ( 4 ), e1000888 ( 2010 ).
  • Bulger M , GroudineM . Functional and mechanistic diversity of distal transcription enhancers . Cell144 ( 3 ), 327 – 339 ( 2011 ).
  • Symmons O , UsluVV , TsujimuraTet al. Functional and topological characteristics of mammalian regulatory domains . Genome Res.24 ( 3 ), 390 – 400 ( 2014 ).
  • De Laat W , DubouleD . Topology of mammalian developmental enhancers and their regulatory landscapes . Nature502 ( 7472 ), 499 – 506 ( 2013 ).
  • Maurano MT , HumbertR , RynesEet al. Systematic localization of common disease-associated variation in regulatory DNA . Science337 ( 6099 ), 1190 – 1195 ( 2012 ).
  • Whyte W-A , OrlandoD-A , HniszDet al. Master transcription factors and mediator establish super-enhancers at key cell identity genes . Cell153 ( 2 ), 307 – 319 ( 2013 ).
  • Loven J , HokeH-A , LinC-Yet al. Selective inhibition of tumor oncogenes by disruption of super-enhancers . Cell153 ( 2 ), 320 – 334 ( 2013 ).
  • Hnisz D , AbrahamB-J , LeeT-Iet al. Super-enhancers in the control of cell identity and disease . Cell155 ( 4 ), 934 – 947 ( 2013 ).
  • Parker SCJ , StitzelML , TaylorDLet al. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants . Proc. Natl Acad. Sci. USA110 ( 44 ), 17921 – 17926 ( 2013 ).
  • Hay D , HughesJR , BabbsCet al. Genetic dissection of the [alpha]-globin super-enhancer in vivo . Nat. Genet.48 ( 8 ), 895 – 903 ( 2016 ).
  • Brown J-D , LinC-Y , DuanQet al. NF-κB directs dynamic super enhancer formation in inflammation and atherogenesis . Mol. Cell56 ( 0 ), 1 – 13 ( 2014 ).
  • Davey CA , SargentDF , LugerK , MaederAW , RichmondTJ . Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 Å resolution . J. Mol. Biol.319 ( 5 ), 1097 – 1113 ( 2002 ).
  • Luger K , MaderAW , RichmondRK , SargentDF , RichmondTJ . Crystal structure of the nucleosome core particle at 2.8 Å resolution . Nature389 ( 6648 ), 251 – 260 ( 1997 ).
  • Tahiliani M , KohKP , ShenYet al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1 . Science324 ( 5929 ), 930 – 935 ( 2009 ).
  • He YF , LiBZ , LiZet al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA . Science333 ( 6047 ), 1303 – 1307 ( 2011 ).
  • Ito S , ShenL , DaiQet al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine . Science333 ( 6047 ), 1300 – 1303 ( 2011 ).
  • Cortellino S , XuJ , SannaiMet al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair . Cell146 ( 1 ), 67 – 79 ( 2011 ).
  • Maiti A , DrohatAC . Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implicatons for active demethylation of CpG sites . J. Biol. Chem.286 ( 41 ), 35334 – 35338 ( 2011 ).
  • Kouzarides T . Chromatin modifications and their function . Cell128 ( 4 ), 693 – 705 ( 2007 ).
  • Hong L , SchrothGP , MatthewsHR , YauP , BradburyEM . Studies of the DNA binding properties of histone H4 amino terminus. Thermal denaturation studies reveal that acetylation markedly reduces the binding constant of the H4 “tail” to DNA . J. Biol. Chem.268 ( 1 ), 305 – 314 ( 1993 ).
  • Campanero MR , ArmstrongMI , FlemingtonEK . CpG methylation as a mechanism for the regulation of E2F activity . Proc. Natl Acad. Sci. USA97 ( 12 ), 6481 – 6486 ( 2000 ).
  • Iguchi-Ariga SM , SchaffnerW . CpG methylation of the cAMP-responsive enhancer/promoter sequence TGACGTCA abolishes specific factor binding as well as transcriptional activation . Genes Dev.3 ( 5 ), 612 – 619 ( 1989 ).
  • Heintzman ND , HonGC , HawkinsRDet al. Histone modifications at human enhancers reflect global cell-type-specific gene expression . Nature459 ( 7243 ), 108 – 112 ( 2009 ).
  • Creyghton MP , ChengAW , WelsteadGGet al. Histone H3K27ac separates active from poised enhancers and predicts developmental state . Proc. Natl Acad. Sci. USA107 ( 50 ), 21931 – 21936 ( 2010 ).
  • Roh T-Y , CuddapahS , ZhaoK . Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping . Genes Dev.19 ( 5 ), 542 – 552 ( 2005 ).
  • Kraushaar DC , JinW , MaunakeaA , AbrahamB , HaM , ZhaoK . Genome-wide incorporation dynamics reveal distinct categories of turnover for the histone variant H3.3 . Genome Biol.14 ( 10 ), 1 – 15 ( 2013 ).
  • Deaton AM , Gómez-RodríguezM , MieczkowskiJet al. Enhancer regions show high histone H3.3 turnover that changes during differentiation . eLife5 , e15316 ( 2016 ).
  • Rada-Iglesias A , BajpaiR , SwigutT , BrugmannSA , FlynnRA , WysockaJ . A unique chromatin signature uncovers early developmental enhancers in humans . Nature470 ( 7333 ), 279 – 283 ( 2011 ).
  • Schnetz MP , HandokoL , Akhtar-ZaidiBet al. CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression . PLoS Genet.6 ( 7 ), e1001023 ( 2010 ).
  • Kadoch C , CopelandRA , KeilhackH . PRC2 and SWI/SNF chromatin remodeling complexes in health and disease . Biochemistry55 ( 11 ), 1600 – 1614 ( 2016 ).
  • Torchy MP , HamicheA , KlaholzBP . Structure and function insights into the NuRD chromatin remodeling complex . Cell. Mol. Life Sci.72 ( 13 ), 2491 – 2507 ( 2015 ).
  • Jang MK , MochizukiK , ZhouM , JeongHS , BradyJN , OzatoK . The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription . Mol. Cell19 ( 4 ), 523 – 534 ( 2005 ).
  • Kaikkonen M-U , SpannN-J , HeinzSet al. Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription . Mol. Cell51 ( 3 ), 310 – 325 ( 2013 ).
  • Zabidi MA , ArnoldCD , SchernhuberKet al. Enhancer-core-promoter specificity separates developmental and housekeeping gene regulation . Nature518 ( 7540 ), 556 – 559 ( 2015 ).
  • Ramsey SA , KlemmSL , ZakDEet al. Uncovering a macrophage transcriptional program by integrating evidence from motif scanning and expression dynamics . PLoS Comput. Biol.4 ( 3 ), e1000021 ( 2008 ).
  • Ostuni R , PiccoloV , BarozziIet al. Latent enhancers activated by stimulation in differentiated cells . Cell152 ( 1–2 ), 157 – 171 ( 2013 ).
  • Hah N , BennerC , ChongL-W , YuRT , DownesM , EvansRM . Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs . Proc. Natl Acad. Sci. USA112 ( 3 ), E297 – E302 ( 2015 ).
  • Schmidt SV , KrebsW , UlasTet al. The transcriptional regulator network of human inflammatory macrophages is defined by open chromatin . Cell Res.26 ( 2 ), 151 – 170 ( 2016 ).
  • Netea MG , QuintinJ , Van Der MeerJW . Trained immunity: a memory for innate host defense . Cell Host Micr.9 ( 5 ), 355 – 361 ( 2011 ).
  • Hertweck A , EvansC-Á , EskandarpourMet al. T-bet activates Th1 genes through mediator and the super elongation complex . Cell Rep.15 ( 12 ), 2756 – 2770 ( 2016 ).
  • Fang Z , HecklauK , GrossFet al. Transcription factor co-occupied regions in the murine genome constitute T-helper-cell subtype-specific enhancers . Eur. J. Immunol.45 ( 11 ), 3150 – 3157 ( 2015 ).
  • Vahedi G , KannoY , FurumotoYet al. Super-enhancers delineate disease-associated regulatory nodes in T cells . Nature520 ( 7548 ), 558 – 562 ( 2015 ).
  • Northrop JK , WellsAD , ShenH . Cutting edge: chromatin remodeling as a molecular basis for the enhanced functionality of memory CD8 T Cells . J. Immunol.181 ( 2 ), 865 – 868 ( 2008 ).
  • Zediak VP , JohnnidisJB , WherryEJ , BergerSL . Cutting edge: persistently open chromatin at effector gene loci in resting memory CD8+ T cells independent of transcriptional status . J. Immunol.186 ( 5 ), 2705 – 2709 ( 2011 ).
  • Messi M , GiacchettoI , NagataK , LanzavecchiaA , NatoliG , SallustoF . Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes . Nat. Immunol.4 ( 1 ), 78 – 86 ( 2003 ).
  • Farh KK-H , MarsonA , ZhuJet al. Genetic and epigenetic fine mapping of causal autoimmune disease variants . Nature518 ( 7539 ), 337 – 343 ( 2015 ).
  • Seumois G , ChavezL , GerasimovaAet al. Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility . Nat. Immunol.15 ( 8 ), 777 – 788 ( 2014 ).
  • Onengut-Gumuscu S , ChenWM , BurrenOet al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers . Nat. Genet.47 ( 4 ), 381 – 386 ( 2015 ).
  • Roberts AR , VecellioM , ChenLet al. An ankylosing spondylitis-associated genetic variant in the IL23R-IL12RB2 intergenic region modulates enhancer activity and is associated with increased Th1-cell differentiation . Ann. Rheum. Dis.75 ( 12 ), 2150 – 2156 ( 2016 ).
  • Weinstein JS , Lezon-GeydaK , MaksimovaYet al. Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes . Blood124 ( 25 ), 3719 – 3729 ( 2014 ).
  • Cavalli G , HayashiM , JinYet al. MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo . Proc. Natl Acad. Sci. USA113 ( 5 ), 1363 – 1368 ( 2016 ).
  • Zeng L , ZhouMM . Bromodomain: an acetyl-lysine binding domain . FEBS Lett.513 ( 1 ), 124 – 128 ( 2002 ).
  • Pinz S , UnserS , RascleA . Signal transducer and activator of transcription STAT5 is recruited to c-Myc super-enhancer . BMC Mol. Biol.17 ( 1 ), 1 – 11 ( 2016 ).
  • Barda S , PazG , YogevLet al. Expression of BET genes in testis of men with different spermatogenic impairments . Fert. Ster.97 ( 1 ), 46 – 52 ( 2012 ).
  • Nicodeme E , JeffreyKL , SchaeferUet al. Suppression of inflammation by a synthetic histone mimic . Nature468 ( 7327 ), 1119 – 1123 ( 2010 ).
  • Ramirez-Carrozzi VR , NazarianAA , LiCCet al. Selective and antagonistic functions of SWI/SNF and Mi-2β nucleosome remodeling complexes during an inflammatory response . Genes Devel.20 ( 3 ), 282 – 296 ( 2006 ).
  • Chen J , WangZ , HuXet al. BET inhibition attenuates Helicobacter pylori–induced inflammatory response by suppressing inflammatory gene transcription and enhancer activation . J. Immunol.196 ( 10 ), 4132 – 4142 ( 2016 ).
  • Dooley KE , WarburtonA , McbrideAA . Tandemly integrated HPV16 can form a Brd4-dependent super-enhancer-like element that drives transcription of viral oncogenes . mBio7 ( 5 ), doi:10.1128/mBio.01446-16 ( 2016 ).
  • Belkina AC , NikolajczykBS , DenisGV . BET protein function Is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1impair mouse macrophageinflammatory responses . J. Immunol.190 ( 7 ), 3670 – 3678 ( 2013 ).
  • Barrett E , BrothersS , WahlestedtC , BeurelEO . I-BET151 selectively regulates IL-6 production . Bioch. Biophy. Acta1842 ( 9 ), 1549 – 1555 ( 2014 ).
  • Wienerroither S , RauchI , RosebrockFet al. Regulation of NO synthesis, local inflammation, and innate immunity to pathogens by BET family proteins . Mol. Cell. Biol.34 ( 3 ), 415 – 427 ( 2014 ).
  • Meng S , ZhangL , TangYet al. BET Inhibitor JQ1 blocks inflammation and bone destruction . J. Dent. Res.93 ( 7 ), 657 – 662 ( 2014 ).
  • Qiao Y , GiannopoulouE-G , ChanC-Het al. Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling . Immunity39 ( 3 ), 454 – 469 ( 2013 ).
  • Chan CH , FangC , QiaoY , YarilinaA , PrinjhaRK , IvashkivLB . BET bromodomain inhibition suppresses transcriptional responses to cytokine-Jak-STAT signaling in a gene-specific manner in human monocytes . Eur. J. Immunol.45 ( 1 ), 287 – 297 ( 2015 ).
  • Toniolo PA , LiuS , YehJEet al. Inhibiting STAT5 by the BET bromodomain inhibitor JQ1 disrupts human dendritic cell maturation . J. Immunol.194 ( 7 ), 3180 – 3190 ( 2015 ).
  • Schilderink R , BellM , ReginatoEet al. BET bromodomain inhibition reduces maturation and enhances tolerogenic properties of human and mouse dendritic cells . Mol. Immunol.79 , 66 – 76 ( 2016 ).
  • Bandukwala HS , GagnonJ , TogherSet al. Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors . Proc. Natl Acad. Sci. USA109 ( 36 ), 14532 – 14537 ( 2012 ).
  • Mele DA , SalmeronA , GhoshS , HuangHR , BryantBM , LoraJM . BET bromodomain inhibition suppresses TH17-mediated pathology . J. Exp. Med.210 ( 11 ), 2181 – 2190 ( 2013 ).
  • Belkina AC , BlantonWP , NikolajczykBS , DenisGV . The double bromodomain protein Brd2 promotes B cell expansion and mitogenesis . J. Leuk. Biol.95 ( 3 ), 451 – 460 ( 2014 ).
  • Stanlie A , YousifAS , AkiyamaH , HonjoT , Begum NasimA . Chromatin reader Brd4 functions in Ig class switching as a repair complex adaptor of nonhomologous end-joining . Mol. Cell55 ( 1 ), 97 – 110 ( 2014 ).
  • Peeters JGC , VervoortSJ , TanSCet al. Inhibition of super-enhancer activity in autoinflammatory site-derived T cells reduces disease-associated gene expression . Cell Rep.12 ( 12 ), 1986 – 1996 ( 2015 ).
  • Michaeloudes C , MercadoN , ClarkeCet al. Bromodomain and extraterminal proteins suppress NF-E2-related factor 2–mediated antioxidant gene expression . J. Immunol.192 ( 10 ), 4913 – 4920 ( 2014 ).
  • Zhang G , LiuR , ZhongYet al. Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition . J. Biol. Chem.287 ( 34 ), 28840 – 28851 ( 2012 ).
  • Nadeem A , Al-HarbiNO , Al-HarbiMMet al. Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC/IL-17A pathway modulation . Pharmacol. Res.99 ( 0 ), 248 – 257 ( 2015 ).
  • Fu W , FaracheJ , ClardySMet al. Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells . eLife3 , e04631 ( 2014 ).
  • Park-Min KH , LimE , LeeMJet al. Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation . Nat. Commun.5 , 5418 ( 2014 ).
  • Zhang QG , QianJ , ZhuYC . Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis . Immunol. Lett.166 ( 2 ), 103 – 108 ( 2015 ).
  • Klein K , KabalaPA , GrabiecAMet al. The bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matrix degrading enzymes in rheumatoid arthritis synovial fibroblasts . Ann. Rheum. Dis.75 ( 2 ), 422 – 429 ( 2014 ).
  • Trerotola M , RelliV , SimeoneP , AlbertiS . Epigenetic inheritance and the missing heritability . Hum. Genomics9 , 17 ( 2015 ).
  • Park J-H , WacholderS , GailMHet al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries . Nat. Genet.42 ( 7 ), 570 – 575 ( 2010 ).