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Targeting transcriptional machinery to inhibit enhancer-driven gene expression in heart failure

  • Rachel A. Minerath
  • Duane D. Hall
  • Chad E. GrueterEmail author
Article
  • 70 Downloads

Abstract

Pathological cardiac remodeling is induced through multiple mechanisms that include neurohumoral and biomechanical stress resulting in transcriptional alterations that ultimately become maladaptive and lead to the development of heart failure (HF). Although cardiac transcriptional remodeling is mediated by the activation of numerous signaling pathways that converge on a limited number of transcription factors (TFs) that promote hypertrophy (pro-hypertrophic TFs), the current therapeutic approach to prevent HF utilizes pharmacological inhibitors that largely target specific receptors that are activated in response to pathological stimuli. Thus, there is limited efficacy with the current pharmacological approaches to inhibit transcriptional remodeling associated with the development of HF. Recent evidence suggests that these pro-hypertrophic TFs co-localize at enhancers to cooperatively activate transcription associated with pathological cardiac remodeling. In disease states, including cancer and HF, evidence suggests that the general transcriptional machinery is disproportionately bound at enhancers. Therefore, pharmacological inhibition of transcriptional machinery that integrates pro-hypertrophic TFs may represent a promising alternative therapeutic approach to limit pathological remodeling associated with the development of HF.

Keywords

Transcription Enhancers Heart failure Epigenetics 

Notes

Acknowledgements

We would like to thank Jennifer Barr for critically editing.

Funding information

This work was supported by generous research support from the National Institutes of Health (NIH) Grant R01-HL-125436, the Fraternal Order of Eagles Diabetes Research Center, and the University of Iowa, Carver College of Medicine (to C. E. Grueter).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Gerlach D, Tontsch-Grunt U, Baum A, Popow J, Scharn D, Hofmann MH, Engelhardt H, Kaya O, Beck J, Schweifer N, Gerstberger T, Zuber J, Savarese F, Kraut N (2018) The novel BET bromodomain inhibitor BI 894999 represses super-enhancer-associated transcription and synergizes with CDK9 inhibition in AML. Oncogene 37(20):2687–2701.  https://doi.org/10.1038/s41388-018-0150-2 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    van Berlo JH, Maillet M, Molkentin JD (2013) Signaling effectors underlying pathologic growth and remodeling of the heart. J Clin Invest 123(1):37–45.  https://doi.org/10.1172/JCI62839 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Taegtmeyer H, Sen S, Vela D (2010) Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. Ann N Y Acad Sci 1188:191–198.  https://doi.org/10.1111/j.1749-6632.2009.05100.x CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Papait R, Cattaneo P, Kunderfranco P, Greco C, Carullo P, Guffanti A, Vigano V, Stirparo GG, Latronico MV, Hasenfuss G, Chen J, Condorelli G (2013) Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy. Proc Natl Acad Sci U S A 110(50):20164–20169.  https://doi.org/10.1073/pnas.1315155110 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sayed D, He M, Yang Z, Lin L, Abdellatif M (2013) Transcriptional regulation patterns revealed by high resolution chromatin immunoprecipitation during cardiac hypertrophy. J Biol Chem 288(4):2546–2558.  https://doi.org/10.1074/jbc.M112.429449 CrossRefPubMedGoogle Scholar
  6. 6.
    Spiltoir JI, Stratton MS, Cavasin MA, Demos-Davies K, Reid BG, Qi J, Bradner JE, McKinsey TA (2013) BET acetyl-lysine binding proteins control pathological cardiac hypertrophy. J Mol Cell Cardiol 63:175–179.  https://doi.org/10.1016/j.yjmcc.2013.07.017 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Anand P, Brown JD, Lin CY, Qi J, Zhang R, Artero PC, Alaiti MA, Bullard J, Alazem K, Margulies KB, Cappola TP, Lemieux M, Plutzky J, Bradner JE, Haldar SM (2013) BET bromodomains mediate transcriptional pause release in heart failure. Cell 154(3):569–582.  https://doi.org/10.1016/j.cell.2013.07.013 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Duan Q, McMahon S, Anand P, Shah H, Thomas S, Salunga HT, Huang Y, Zhang R, Sahadevan A, Lemieux ME, Brown JD, Srivastava D, Bradner JE, McKinsey TA, Haldar SM (2017) BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure. Sci Transl Med 9(390).  https://doi.org/10.1126/scitranslmed.aah5084
  9. 9.
    Sun Y, Xie Y, Du L, Sun J, Liu Z (2018) Inhibition of BRD4 attenuates cardiomyocyte apoptosis via NF-kappaB pathway in a rat model of myocardial infarction. Cardiovasc Ther 36 (2). doi: https://doi.org/10.1111/1755-5922.12320
  10. 10.
    Sano M, Abdellatif M, Oh H, Xie M, Bagella L, Giordano A, Michael LH, DeMayo FJ, Schneider MD (2002) Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy. Nat Med 8(11):1310–1317.  https://doi.org/10.1038/nm778 CrossRefPubMedGoogle Scholar
  11. 11.
    Kee HJ, Sohn IS, Nam KI, Park JE, Qian YR, Yin Z, Ahn Y, Jeong MH, Bang YJ, Kim N, Kim JK, Kim KK, Epstein JA, Kook H (2006) Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation 113(1):51–59.  https://doi.org/10.1161/CIRCULATIONAHA.105.559724 CrossRefPubMedGoogle Scholar
  12. 12.
    Kook H, Lepore JJ, Gitler AD, Lu MM, Wing-Man Yung W, Mackay J, Zhou R, Ferrari V, Gruber P, Epstein JA (2003) Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. J Clin Invest 112(6):863–871.  https://doi.org/10.1172/JCI19137 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kong Y, Tannous P, Lu G, Berenji K, Rothermel BA, Olson EN, Hill JA (2006) Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation 113(22):2579–2588.  https://doi.org/10.1161/CIRCULATIONAHA.106.625467 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gallo P, Latronico MV, Gallo P, Grimaldi S, Borgia F, Todaro M, Jones P, Gallinari P, De Francesco R, Ciliberto G, Steinkuhler C, Esposito G, Condorelli G (2008) Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure. Cardiovasc Res 80(3):416–424.  https://doi.org/10.1093/cvr/cvn215 CrossRefPubMedGoogle Scholar
  15. 15.
    Granger A, Abdullah I, Huebner F, Stout A, Wang T, Huebner T, Epstein JA, Gruber PJ (2008) Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J 22(10):3549–3560.  https://doi.org/10.1096/fj.08-108548 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lee TM, Lin MS, Chang NC (2007) Inhibition of histone deacetylase on ventricular remodeling in infarcted rats. Am J Physiol Heart Circ Physiol 293(2):H968–H977.  https://doi.org/10.1152/ajpheart.00891.2006 CrossRefPubMedGoogle Scholar
  17. 17.
    Zhao TC, Cheng G, Zhang LX, Tseng YT, Padbury JF (2007) Inhibition of histone deacetylases triggers pharmacologic preconditioning effects against myocardial ischemic injury. Cardiovasc Res 76(3):473–481.  https://doi.org/10.1016/j.cardiores.2007.08.010 CrossRefPubMedGoogle Scholar
  18. 18.
    Consortium EP (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489(7414):57–74.  https://doi.org/10.1038/nature11247 CrossRefGoogle Scholar
  19. 19.
    Sanyal A, Lajoie BR, Jain G, Dekker J (2012) The long-range interaction landscape of gene promoters. Nature 489(7414):109–113.  https://doi.org/10.1038/nature11279 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lettice LA, Heaney SJ, Purdie LA, Li L, de Beer P, Oostra BA, Goode D, Elgar G, Hill RE, de Graaff E (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 12(14):1725–1735CrossRefPubMedGoogle Scholar
  21. 21.
    Nobrega MA, Ovcharenko I, Afzal V, Rubin EM (2003) Scanning human gene deserts for long-range enhancers. Science 302(5644):413.  https://doi.org/10.1126/science.1088328 CrossRefPubMedGoogle Scholar
  22. 22.
    Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA (2013) Master transcription factors and Mediator establish super-enhancers at key cell identity genes. Cell 153(2):307–319.  https://doi.org/10.1016/j.cell.2013.03.035 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Panne D (2008) The enhanceosome. Curr Opin Struct Biol 18(2):236–242.  https://doi.org/10.1016/j.sbi.2007.12.002 CrossRefPubMedGoogle Scholar
  24. 24.
    Carey M (1998) The enhanceosome and transcriptional synergy. Cell 92(1):5–8CrossRefPubMedGoogle Scholar
  25. 25.
    He A, Kong SW, Ma Q, Pu WT (2011) Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart. Proc Natl Acad Sci U S A 108(14):5632–5637.  https://doi.org/10.1073/pnas.1016959108 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Shin HY (2018) Targeting super-enhancers for disease treatment and diagnosis. Mol Cell 41(6):506–514.  https://doi.org/10.14348/molcells.2018.2297 CrossRefGoogle Scholar
  27. 27.
    Ounzain S, Pedrazzini T (2016) Super-enhancer lncs to cardiovascular development and disease. Biochim Biophys Acta 1863(7 Pt B):1953–1960.  https://doi.org/10.1016/j.bbamcr.2015.11.026 CrossRefPubMedGoogle Scholar
  28. 28.
    Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, Hanna J, Lodato MA, Frampton GM, Sharp PA, Boyer LA, Young RA, Jaenisch R (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A 107(50):21931–21936.  https://doi.org/10.1073/pnas.1016071107 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP, Lee W, Mendenhall E, O’Donovan A, Presser A, Russ C, Xie X, Meissner A, Wernig M, Jaenisch R, Nusbaum C, Lander ES, Bernstein BE (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448(7153):553–560.  https://doi.org/10.1038/nature06008 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Guenther MG, Levine SS, Boyer LA, Jaenisch R, Young RA (2007) A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130(1):77–88.  https://doi.org/10.1016/j.cell.2007.05.042 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bernstein BE, Kamal M, Lindblad-Toh K, Bekiranov S, Bailey DK, Huebert DJ, McMahon S, Karlsson EK, Kulbokas EJ 3rd, Gingeras TR, Schreiber SL, Lander ES (2005) Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120(2):169–181.  https://doi.org/10.1016/j.cell.2005.01.001 CrossRefPubMedGoogle Scholar
  32. 32.
    Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, Barrera LO, Van Calcar S, Qu C, Ching KA, Wang W, Weng Z, Green RD, Crawford GE, Ren B (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39(3):311–318.  https://doi.org/10.1038/ng1966 CrossRefPubMedGoogle Scholar
  33. 33.
    Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB, Zhang X, Wang L, Issner R, Coyne M, Ku M, Durham T, Kellis M, Bernstein BE (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473(7345):43–49.  https://doi.org/10.1038/nature09906 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Visel A, Rubin EM, Pennacchio LA (2009) Genomic views of distant-acting enhancers. Nature 461(7261):199–205.  https://doi.org/10.1038/nature08451 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    May D, Blow MJ, Kaplan T, McCulley DJ, Jensen BC, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Afzal V, Simpson PC, Rubin EM, Black BL, Bristow J, Pennacchio LA, Visel A (2011) Large-scale discovery of enhancers from human heart tissue. Nat Genet 44(1):89–93.  https://doi.org/10.1038/ng.1006 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Blow MJ, McCulley DJ, Li Z, Zhang T, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Chen F, Afzal V, Bristow J, Ren B, Black BL, Rubin EM, Visel A, Pennacchio LA (2010) ChIP-Seq identification of weakly conserved heart enhancers. Nat Genet 42(9):806–810.  https://doi.org/10.1038/ng.650 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Narlikar L, Sakabe NJ, Blanski AA, Arimura FE, Westlund JM, Nobrega MA, Ovcharenko I (2010) Genome-wide discovery of human heart enhancers. Genome Res 20(3):381–392.  https://doi.org/10.1101/gr.098657.109 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-Andre V, Sigova AA, Hoke HA, Young RA (2013) Super-enhancers in the control of cell identity and disease. Cell 155(4):934–947.  https://doi.org/10.1016/j.cell.2013.09.053 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, Sheffield NC, Stergachis AB, Wang H, Vernot B, Garg K, John S, Sandstrom R, Bates D, Boatman L, Canfield TK, Diegel M, Dunn D, Ebersol AK, Frum T, Giste E, Johnson AK, Johnson EM, Kutyavin T, Lajoie B, Lee BK, Lee K, London D, Lotakis D, Neph S, Neri F, Nguyen ED, Qu H, Reynolds AP, Roach V, Safi A, Sanchez ME, Sanyal A, Shafer A, Simon JM, Song L, Vong S, Weaver M, Yan Y, Zhang Z, Zhang Z, Lenhard B, Tewari M, Dorschner MO, Hansen RS, Navas PA, Stamatoyannopoulos G, Iyer VR, Lieb JD, Sunyaev SR, Akey JM, Sabo PJ, Kaul R, Furey TS, Dekker J, Crawford GE, Stamatoyannopoulos JA (2012) The accessible chromatin landscape of the human genome. Nature 489(7414):75–82.  https://doi.org/10.1038/nature11232 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Pott S, Lieb JD (2015) What are super-enhancers? Nat Genet 47(1):8–12.  https://doi.org/10.1038/ng.3167 CrossRefPubMedGoogle Scholar
  41. 41.
    Adam RC, Yang H, Rockowitz S, Larsen SB, Nikolova M, Oristian DS, Polak L, Kadaja M, Asare A, Zheng D, Fuchs E (2015) Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. Nature 521(7552):366–370.  https://doi.org/10.1038/nature14289 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Brown JD, Lin CY, Duan Q, Griffin G, Federation A, Paranal RM, Bair S, Newton G, Lichtman A, Kung A, Yang T, Wang H, Luscinskas FW, Croce K, Bradner JE, Plutzky J (2014) NF-kappaB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol Cell 56(2):219–231.  https://doi.org/10.1016/j.molcel.2014.08.024 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, Tang Z, Ruan Y, Collins FS, Sartorelli V, O’Shea JJ (2015) Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature 520(7548):558–562.  https://doi.org/10.1038/nature14154 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Pelish HE, Liau BB, Nitulescu II, Tangpeerachaikul A, Poss ZC, Da Silva DH, Caruso BT, Arefolov A, Fadeyi O, Christie AL, Du K, Banka D, Schneider EV, Jestel A, Zou G, Si C, Ebmeier CC, Bronson RT, Krivtsov AV, Myers AG, Kohl NE, Kung AL, Armstrong SA, Lemieux ME, Taatjes DJ, Shair MD (2015) Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature 526(7572):273–276.  https://doi.org/10.1038/nature14904 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Affer M, Chesi M, Chen WG, Keats JJ, Demchenko YN, Roschke AV, Van Wier S, Fonseca R, Bergsagel PL, Kuehl WM (2014) Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia 28(8):1725–1735.  https://doi.org/10.1038/leu.2014.70 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Walker BA, Wardell CP, Brioli A, Boyle E, Kaiser MF, Begum DB, Dahir NB, Johnson DC, Ross FM, Davies FE, Morgan GJ (2014) Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood Cancer J 4:e191.  https://doi.org/10.1038/bcj.2014.13 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Oka T, Xu J, Molkentin JD (2007) Re-employment of developmental transcription factors in adult heart disease. Semin Cell Dev Biol 18(1):117–131.  https://doi.org/10.1016/j.semcdb.2006.11.012 CrossRefPubMedGoogle Scholar
  48. 48.
    Akazawa H, Komuro I (2003) Roles of cardiac transcription factors in cardiac hypertrophy. Circ Res 92(10):1079–1088.  https://doi.org/10.1161/01.RES.0000072977.86706.23 CrossRefPubMedGoogle Scholar
  49. 49.
    Schlesinger J, Schueler M, Grunert M, Fischer JJ, Zhang Q, Krueger T, Lange M, Tonjes M, Dunkel I, Sperling SR (2011) The cardiac transcription network modulated by Gata4, Mef2a, Nkx2.5, Srf, histone modifications, and microRNAs. PLoS Genet 7(2):e1001313.  https://doi.org/10.1371/journal.pgen.1001313 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Dickel DE, Barozzi I, Zhu Y, Fukuda-Yuzawa Y, Osterwalder M, Mannion BJ, May D, Spurrell CH, Plajzer-Frick I, Pickle CS, Lee E, Garvin TH, Kato M, Akiyama JA, Afzal V, Lee AY, Gorkin DU, Ren B, Rubin EM, Visel A, Pennacchio LA (2016) Genome-wide compendium and functional assessment of in vivo heart enhancers. Nat Commun 7:12923.  https://doi.org/10.1038/ncomms12923 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Wamstad JA, Alexander JM, Truty RM, Shrikumar A, Li F, Eilertson KE, Ding H, Wylie JN, Pico AR, Capra JA, Erwin G, Kattman SJ, Keller GM, Srivastava D, Levine SS, Pollard KS, Holloway AK, Boyer LA, Bruneau BG (2012) Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Cell 151(1):206–220.  https://doi.org/10.1016/j.cell.2012.07.035 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Stergachis AB, Neph S, Reynolds A, Humbert R, Miller B, Paige SL, Vernot B, Cheng JB, Thurman RE, Sandstrom R, Haugen E, Heimfeld S, Murry CE, Akey JM, Stamatoyannopoulos JA (2013) Developmental fate and cellular maturity encoded in human regulatory DNA landscapes. Cell 154(4):888–903.  https://doi.org/10.1016/j.cell.2013.07.020 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    He A, Gu F, Hu Y, Ma Q, Ye LY, Akiyama JA, Visel A, Pennacchio LA, Pu WT (2014) Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease. Nat Commun 5:4907.  https://doi.org/10.1038/ncomms5907 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ounzain S, Pezzuto I, Micheletti R, Burdet F, Sheta R, Nemir M, Gonzales C, Sarre A, Alexanian M, Blow MJ, May D, Johnson R, Dauvillier J, Pennacchio LA, Pedrazzini T (2014) Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease. J Mol Cell Cardiol 76:55–70.  https://doi.org/10.1016/j.yjmcc.2014.08.009 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Anderson CM, Hu J, Thomas R, Gainous TB, Celona B, Sinha T, Dickel DE, Heidt AB, Xu SM, Bruneau BG, Pollard KS, Pennacchio LA, Black BL (2017) Cooperative activation of cardiac transcription through myocardin bridging of paired MEF2 sites. Development 144(7):1235–1241.  https://doi.org/10.1242/dev.138487 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Junion G, Spivakov M, Girardot C, Braun M, Gustafson EH, Birney E, Furlong EE (2012) A transcription factor collective defines cardiac cell fate and reflects lineage history. Cell 148(3):473–486.  https://doi.org/10.1016/j.cell.2012.01.030 CrossRefPubMedGoogle Scholar
  57. 57.
    Lelli KM, Slattery M, Mann RS (2012) Disentangling the many layers of eukaryotic transcriptional regulation. Annu Rev Genet 46:43–68.  https://doi.org/10.1146/annurev-genet-110711-155437 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Spitz F, Furlong EE (2012) Transcription factors: from enhancer binding to developmental control. Nat Rev Genet 13(9):613–626.  https://doi.org/10.1038/nrg3207 CrossRefPubMedGoogle Scholar
  59. 59.
    Siersbaek R, Rabiee A, Nielsen R, Sidoli S, Traynor S, Loft A, Poulsen LC, Rogowska-Wrzesinska A, Jensen ON, Mandrup S (2014) Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep 7(5):1443–1455.  https://doi.org/10.1016/j.celrep.2014.04.042 CrossRefPubMedGoogle Scholar
  60. 60.
    Lien CL, McAnally J, Richardson JA, Olson EN (2002) Cardiac-specific activity of an Nkx2-5 enhancer requires an evolutionarily conserved Smad binding site. Dev Biol 244(2):257–266.  https://doi.org/10.1006/dbio.2002.0603 CrossRefPubMedGoogle Scholar
  61. 61.
    Lickert H, Takeuchi JK, Von Both I, Walls JR, McAuliffe F, Adamson SL, Henkelman RM, Wrana JL, Rossant J, Bruneau BG (2004) Baf60c is essential for function of BAF chromatin remodelling complexes in heart development. Nature 432(7013):107–112.  https://doi.org/10.1038/nature03071 CrossRefPubMedGoogle Scholar
  62. 62.
    McKinsey TA (2012) Therapeutic potential for HDAC inhibitors in the heart. Annu Rev Pharmacol Toxicol 52:303–319.  https://doi.org/10.1146/annurev-pharmtox-010611-134712 CrossRefPubMedGoogle Scholar
  63. 63.
    McKinsey TA, Zhang CL, Olson EN (2002) MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci 27(1):40–47CrossRefPubMedGoogle Scholar
  64. 64.
    Kim YJ, Greer CB, Cecchini KR, Harris LN, Tuck DP, Kim TH (2013) HDAC inhibitors induce transcriptional repression of high copy number genes in breast cancer through elongation blockade. Oncogene 32(23):2828–2835.  https://doi.org/10.1038/onc.2013.32 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Greer CB, Tanaka Y, Kim YJ, Xie P, Zhang MQ, Park IH, Kim TH (2015) Histone deacetylases positively regulate transcription through the elongation machinery. Cell Rep 13(7):1444–1455.  https://doi.org/10.1016/j.celrep.2015.10.013 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6(1):38–51.  https://doi.org/10.1038/nrc1779 CrossRefPubMedGoogle Scholar
  67. 67.
    Chen H, Lin RJ, Xie W, Wilpitz D, Evans RM (1999) Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell 98(5):675–686CrossRefPubMedGoogle Scholar
  68. 68.
    Wolf D, Rodova M, Miska EA, Calvet JP, Kouzarides T (2002) Acetylation of beta-catenin by CREB-binding protein (CBP). J Biol Chem 277(28):25562–25567.  https://doi.org/10.1074/jbc.M201196200 CrossRefPubMedGoogle Scholar
  69. 69.
    Chandrasekaran S, Peterson RE, Mani SK, Addy B, Buchholz AL, Xu L, Thiyagarajan T, Kasiganesan H, Kern CB, Menick DR (2009) Histone deacetylases facilitate sodium/calcium exchanger up-regulation in adult cardiomyocytes. FASEB J 23(11):3851–3864.  https://doi.org/10.1096/fj.09-132415 CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Jeong MY, Lin YH, Wennersten SA, Demos-Davies KM, Cavasin MA, Mahaffey JH, Monzani V, Saripalli C, Mascagni P, Reece TB, Ambardekar AV, Granzier HL, Dinarello CA, McKinsey TA (2018) Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Sci Transl Med 10(427).  https://doi.org/10.1126/scitranslmed.aao0144
  71. 71.
    McKinsey TA, Olson EN (2005) Toward transcriptional therapies for the failing heart: chemical screens to modulate genes. J Clin Invest 115(3):538–546.  https://doi.org/10.1172/JCI24144 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Yang Z, Yik JH, Chen R, He N, Jang MK, Ozato K, Zhou Q (2005) Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell 19(4):535–545.  https://doi.org/10.1016/j.molcel.2005.06.029 CrossRefPubMedGoogle Scholar
  73. 73.
    Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE (2010) Selective inhibition of BET bromodomains. Nature 468(7327):1067–1073.  https://doi.org/10.1038/nature09504 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, Young RA (2013) Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153(2):320–334.  https://doi.org/10.1016/j.cell.2013.03.036 CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Chapuy B, McKeown MR, Lin CY, Monti S, Roemer MG, Qi J, Rahl PB, Sun HH, Yeda KT, Doench JG, Reichert E, Kung AL, Rodig SJ, Young RA, Shipp MA, Bradner JE (2013) Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell 24(6):777–790.  https://doi.org/10.1016/j.ccr.2013.11.003 CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Groschel S, Sanders MA, Hoogenboezem R, de Wit E, Bouwman BAM, Erpelinck C, van der Velden VHJ, Havermans M, Avellino R, van Lom K, Rombouts EJ, van Duin M, Dohner K, Beverloo HB, Bradner JE, Dohner H, Lowenberg B, Valk PJM, Bindels EMJ, de Laat W, Delwel R (2014) A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell 157(2):369–381.  https://doi.org/10.1016/j.cell.2014.02.019 CrossRefPubMedGoogle Scholar
  77. 77.
    Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades CS (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146(6):904–917.  https://doi.org/10.1016/j.cell.2011.08.017 CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, Vakoc CR (2011) RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478(7370):524–528.  https://doi.org/10.1038/nature10334 CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Stratton MS, Lin CY, Anand P, Tatman PD, Ferguson BS, Wickers ST, Ambardekar AV, Sucharov CC, Bradner JE, Haldar SM, McKinsey TA (2016) Signal-dependent recruitment of BRD4 to cardiomyocyte super-enhancers is suppressed by a microRNA. Cell Rep 16(5):1366–1378.  https://doi.org/10.1016/j.celrep.2016.06.074 CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Malik S, Roeder RG (2010) The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation. Nat Rev Genet 11(11):761–772.  https://doi.org/10.1038/nrg2901 CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    D’Alessio JA, Wright KJ, Tjian R (2009) Shifting players and paradigms in cell-specific transcription. Mol Cell 36(6):924–931.  https://doi.org/10.1016/j.molcel.2009.12.011 CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Deato MD, Marr MT, Sottero T, Inouye C, Hu P, Tjian R (2008) MyoD targets TAF3/TRF3 to activate myogenin transcription. Mol Cell 32(1):96–105.  https://doi.org/10.1016/j.molcel.2008.09.009 CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Hall DD, Ponce JM, Chen B, Spitler KM, Alexia A, Oudit GY, Song LS, Grueter CE (2017) Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure. JCI Insight 2(15):92476.  https://doi.org/10.1172/jci.insight.92476 CrossRefPubMedGoogle Scholar
  84. 84.
    Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, van Berkum NL, Ebmeier CC, Goossens J, Rahl PB, Levine SS, Taatjes DJ, Dekker J, Young RA (2010) Mediator and cohesin connect gene expression and chromatin architecture. Nature 467(7314):430–435.  https://doi.org/10.1038/nature09380 CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Borik S, Simon AJ, Nevo-Caspi Y, Mishali D, Amariglio N, Rechavi G, Paret G (2011) Increased RNA editing in children with cyanotic congenital heart disease. Intensive Care Med 37(10):1664–1671.  https://doi.org/10.1007/s00134-011-2296-z CrossRefPubMedGoogle Scholar
  86. 86.
    Muncke N, Jung C, Rudiger H, Ulmer H, Roeth R, Hubert A, Goldmuntz E, Driscoll D, Goodship J, Schon K, Rappold G (2003) Missense mutations and gene interruption in PROSIT240, a novel TRAP240-like gene, in patients with congenital heart defect (transposition of the great arteries). Circulation 108(23):2843–2850.  https://doi.org/10.1161/01.CIR.0000103684.77636.CD CrossRefPubMedGoogle Scholar
  87. 87.
    Asadollahi R, Oneda B, Sheth F, Azzarello-Burri S, Baldinger R, Joset P, Latal B, Knirsch W, Desai S, Baumer A, Houge G, Andrieux J, Rauch A (2013) Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability. Eur J Hum Genet 21(10):1100–1104.  https://doi.org/10.1038/ejhg.2013.17 CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Chen CP, Chen YY, Chern SR, Wu PS, Su JW, Chen YT, Chen LF, Wang W (2013) Prenatal diagnosis and molecular cytogenetic characterization of de novo partial trisomy 12q (12q24.21-->qter) and partial monosomy 6q (6q27-->qter) associated with coarctation of the aorta, ventriculomegaly and thickened nuchal fold. Gene 516(1):138–142.  https://doi.org/10.1016/j.gene.2012.12.051 CrossRefPubMedGoogle Scholar
  89. 89.
    Kobrynski LJ, Sullivan KE (2007) Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet 370(9596):1443–1452.  https://doi.org/10.1016/S0140-6736(07)61601-8 CrossRefPubMedGoogle Scholar
  90. 90.
    Jia Y, Chang HC, Schipma MJ, Liu J, Shete V, Liu N, Sato T, Thorp EB, Barger PM, Zhu YJ, Viswakarma N, Kanwar YS, Ardehali H, Thimmapaya B, Reddy JK (2016) Cardiomyocyte-specific ablation of Med1 subunit of the Mediator complex causes lethal dilated cardiomyopathy in mice. PLoS One 11(8):e0160755.  https://doi.org/10.1371/journal.pone.0160755 CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Spitler KM, Ponce JM, Oudit GY, Hall DD, Grueter CE (2017) Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming. Am J Physiol Heart Circ Physiol 312(4):H768–H780.  https://doi.org/10.1152/ajpheart.00728.2016 CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Hall DD, Spitler KM, Grueter CE (2018) Disruption of cardiac Med1 inhibits RNA polymerase-II promoter occupancy and promotes chromatin remodeling. Am J Physiol Heart Circ Physiol.  https://doi.org/10.1152/ajpheart.00580.2018
  93. 93.
    Baskin KK, Makarewich CA, DeLeon SM, Ye W, Chen B, Beetz N, Schrewe H, Bassel-Duby R, Olson EN (2017) MED12 regulates a transcriptional network of calcium-handling genes in the heart. JCI Insight 2(14):91920.  https://doi.org/10.1172/jci.insight.91920 CrossRefPubMedGoogle Scholar
  94. 94.
    Baskin KK, Grueter CE, Kusminski CM, Holland WL, Bookout AL, Satapati S, Kong YM, Burgess SC, Malloy CR, Scherer PE, Newgard CB, Bassel-Duby R, Olson EN (2014) MED13-dependent signaling from the heart confers leanness by enhancing metabolism in adipose tissue and liver. EMBO Mol Med 6(12):1610–1621.  https://doi.org/10.15252/emmm.201404218 CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Grueter CE, van Rooij E, Johnson BA, DeLeon SM, Sutherland LB, Qi X, Gautron L, Elmquist JK, Bassel-Duby R, Olson EN (2012) A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. Cell 149(3):671–683.  https://doi.org/10.1016/j.cell.2012.03.029 CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Minerath RA, Dewey CM, Hall DD, Grueter CE (2019) Regulation of cardiac transcription by thyroid hormone and Med13. J Mol Cell Cardiol 129:27–38.  https://doi.org/10.1016/j.yjmcc.2019.01.007 CrossRefPubMedGoogle Scholar
  97. 97.
    Aranda-Orgilles B, Saldana-Meyer R, Wang E, Trompouki E, Fassl A, Lau S, Mullenders J, Rocha PP, Raviram R, Guillamot M, Sanchez-Diaz M, Wang K, Kayembe C, Zhang N, Amoasii L, Choudhuri A, Skok JA, Schober M, Reinberg D, Sicinski P, Schrewe H, Tsirigos A, Zon LI, Aifantis I (2016) MED12 regulates HSC-specific enhancers independently of Mediator kinase activity to control hematopoiesis. Cell Stem Cell 19(6):784–799.  https://doi.org/10.1016/j.stem.2016.08.004 CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Kuuluvainen E, Domenech-Moreno E, Niemela EH, Makela TP (2018) Depletion of Mediator kinase module subunits represses superenhancer-associated genes in colon cancer cells. Mol Cell Biol 38(11):e00573–e00517.  https://doi.org/10.1128/MCB.00573-17 CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Bhagwat AS, Roe JS, Mok BYL, Hohmann AF, Shi J, Vakoc CR (2016) BET Bromodomain inhibition releases the Mediator complex from select cis-regulatory elements. Cell Rep 15(3):519–530.  https://doi.org/10.1016/j.celrep.2016.03.054 CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Galbraith MD, Donner AJ, Espinosa JM (2010) CDK8: a positive regulator of transcription. Transcription 1(1):4–12.  https://doi.org/10.4161/trns.1.1.12373 CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Elmlund H, Baraznenok V, Lindahl M, Samuelsen CO, Koeck PJ, Holmberg S, Hebert H, Gustafsson CM (2006) The cyclin-dependent kinase 8 module sterically blocks Mediator interactions with RNA polymerase II. Proc Natl Acad Sci U S A 103(43):15788–15793.  https://doi.org/10.1073/pnas.0607483103 CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Donner AJ, Ebmeier CC, Taatjes DJ, Espinosa JM (2010) CDK8 is a positive regulator of transcriptional elongation within the serum response network. Nat Struct Mol Biol 17(2):194–201.  https://doi.org/10.1038/nsmb.1752 CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Galbraith MD, Allen MA, Bensard CL, Wang X, Schwinn MK, Qin B, Long HW, Daniels DL, Hahn WC, Dowell RD, Espinosa JM (2013) HIF1A employs CDK8-Mediator to stimulate RNAPII elongation in response to hypoxia. Cell 153(6):1327–1339.  https://doi.org/10.1016/j.cell.2013.04.048 CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Chen M, Liang J, Ji H, Yang Z, Altilia S, Hu B, Schronce A, McDermott MSJ, Schools GP, Lim CU, Oliver D, Shtutman MS, Lu T, Stark GR, Porter DC, Broude EV, Roninson IB (2017) CDK8/19 Mediator kinases potentiate induction of transcription by NFkappaB. Proc Natl Acad Sci U S A 114(38):10208–10213.  https://doi.org/10.1073/pnas.1710467114 CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Galbraith MD, Andrysik Z, Pandey A, Hoh M, Bonner EA, Hill AA, Sullivan KD, Espinosa JM (2017) CDK8 kinase activity promotes glycolysis. Cell Rep 21(6):1495–1506.  https://doi.org/10.1016/j.celrep.2017.10.058 CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Belakavadi M, Fondell JD (2010) Cyclin-dependent kinase 8 positively cooperates with Mediator to promote thyroid hormone receptor-dependent transcriptional activation. Mol Cell Biol 30(10):2437–2448.  https://doi.org/10.1128/MCB.01541-09 CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Firestein R, Bass AJ, Kim SY, Dunn IF, Silver SJ, Guney I, Freed E, Ligon AH, Vena N, Ogino S, Chheda MG, Tamayo P, Finn S, Shrestha Y, Boehm JS, Jain S, Bojarski E, Mermel C, Barretina J, Chan JA, Baselga J, Tabernero J, Root DE, Fuchs CS, Loda M, Shivdasani RA, Meyerson M, Hahn WC (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature 455(7212):547–551.  https://doi.org/10.1038/nature07179 CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Morris EJ, Ji JY, Yang F, Di Stefano L, Herr A, Moon NS, Kwon EJ, Haigis KM, Naar AM, Dyson NJ (2008) E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature 455(7212):552–556.  https://doi.org/10.1038/nature07310 CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Alarcon C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S, Barlas A, Miller AN, Manova-Todorova K, Macias MJ, Sapkota G, Pan D, Massague J (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139(4):757–769.  https://doi.org/10.1016/j.cell.2009.09.035 CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Bancerek J, Poss ZC, Steinparzer I, Sedlyarov V, Pfaffenwimmer T, Mikulic I, Dolken L, Strobl B, Muller M, Taatjes DJ, Kovarik P (2013) CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity 38(2):250–262.  https://doi.org/10.1016/j.immuni.2012.10.017 CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Aragon E, Goerner N, Zaromytidou AI, Xi Q, Escobedo A, Massague J, Macias MJ (2011) A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev 25(12):1275–1288.  https://doi.org/10.1101/gad.2060811 CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Zhao X, Feng D, Wang Q, Abdulla A, Xie XJ, Zhou J, Sun Y, Yang ES, Liu LP, Vaitheesvaran B, Bridges L, Kurland IJ, Strich R, Ni JQ, Wang C, Ericsson J, Pessin JE, Ji JY, Yang F (2012) Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1. J Clin Invest 122(7):2417–2427.  https://doi.org/10.1172/JCI61462 CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Poss ZC, Ebmeier CC, Odell AT, Tangpeerachaikul A, Lee T, Pelish HE, Shair MD, Dowell RD, Old WM, Taatjes DJ (2016) Identification of Mediator kinase substrates in human cells using cortistatin A and quantitative phosphoproteomics. Cell Rep 15(2):436–450.  https://doi.org/10.1016/j.celrep.2016.03.030 CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Knuesel MT, Meyer KD, Donner AJ, Espinosa JM, Taatjes DJ (2009) The human CDK8 subcomplex is a histone kinase that requires Med12 for activity and can function independently of Mediator. Mol Cell Biol 29(3):650–661.  https://doi.org/10.1128/MCB.00993-08 CrossRefPubMedGoogle Scholar
  115. 115.
    Meyer KD, Donner AJ, Knuesel MT, York AG, Espinosa JM, Taatjes DJ (2008) Cooperative activity of cdk8 and GCN5L within Mediator directs tandem phosphoacetylation of histone H3. EMBO J 27(10):1447–1457.  https://doi.org/10.1038/emboj.2008.78 CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Akoulitchev S, Chuikov S, Reinberg D (2000) TFIIH is negatively regulated by cdk8-containing Mediator complexes. Nature 407(6800):102–106.  https://doi.org/10.1038/35024111 CrossRefPubMedGoogle Scholar
  117. 117.
    Kapoor A, Goldberg MS, Cumberland LK, Ratnakumar K, Segura MF, Emanuel PO, Menendez S, Vardabasso C, Leroy G, Vidal CI, Polsky D, Osman I, Garcia BA, Hernando E, Bernstein E (2010) The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature 468(7327):1105–1109.  https://doi.org/10.1038/nature09590 CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Donner AJ, Szostek S, Hoover JM, Espinosa JM (2007) CDK8 is a stimulus-specific positive coregulator of p53 target genes. Mol Cell 27(1):121–133.  https://doi.org/10.1016/j.molcel.2007.05.026 CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Nemet J, Jelicic B, Rubelj I, Sopta M (2014) The two faces of Cdk8, a positive/negative regulator of transcription. Biochimie 97:22–27.  https://doi.org/10.1016/j.biochi.2013.10.004 CrossRefPubMedGoogle Scholar
  120. 120.
    Dale T, Clarke PA, Esdar C, Waalboer D, Adeniji-Popoola O, Ortiz-Ruiz MJ, Mallinger A, Samant RS, Czodrowski P, Musil D, Schwarz D, Schneider K, Stubbs M, Ewan K, Fraser E, TePoele R, Court W, Box G, Valenti M, de Haven Brandon A, Gowan S, Rohdich F, Raynaud F, Schneider R, Poeschke O, Blaukat A, Workman P, Schiemann K, Eccles SA, Wienke D, Blagg J (2015) A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nat Chem Biol 11(12):973–980.  https://doi.org/10.1038/nchembio.1952 CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Rzymski T, Mikula M, Zylkiewicz E, Dreas A, Wiklik K, Golas A, Wojcik K, Masiejczyk M, Wrobel A, Dolata I, Kitlinska A, Statkiewicz M, Kuklinska U, Goryca K, Sapala L, Grochowska A, Cabaj A, Szajewska-Skuta M, Gabor-Worwa E, Kucwaj K, Bialas A, Radzimierski A, Combik M, Woyciechowski J, Mikulski M, Windak R, Ostrowski J, Brzozka K (2017) SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains. Oncotarget 8(20):33779–33795.  https://doi.org/10.18632/oncotarget.16810 CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Porter DC, Farmaki E, Altilia S, Schools GP, West DK, Chen M, Chang BD, Puzyrev AT, Lim CU, Rokow-Kittell R, Friedhoff LT, Papavassiliou AG, Kalurupalle S, Hurteau G, Shi J, Baran PS, Gyorffy B, Wentland MP, Broude EV, Kiaris H, Roninson IB (2012) Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities. Proc Natl Acad Sci U S A 109(34):13799–13804.  https://doi.org/10.1073/pnas.1206906109 CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Schuller R, Forne I, Straub T, Schreieck A, Texier Y, Shah N, Decker TM, Cramer P, Imhof A, Eick D (2016) Heptad-specific phosphorylation of RNA polymerase II CTD. Mol Cell 61(2):305–314.  https://doi.org/10.1016/j.molcel.2015.12.003 CrossRefPubMedGoogle Scholar
  124. 124.
    Wada T, Takagi T, Yamaguchi Y, Watanabe D, Handa H (1998) Evidence that P-TEFb alleviates the negative effect of DSIF on RNA polymerase II-dependent transcription in vitro. EMBO J 17(24):7395–7403.  https://doi.org/10.1093/emboj/17.24.7395 CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Price DH (2000) P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol Cell Biol 20(8):2629–2634CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Taube R, Lin X, Irwin D, Fujinaga K, Peterlin BM (2002) Interaction between P-TEFb and the C-terminal domain of RNA polymerase II activates transcriptional elongation from sites upstream or downstream of target genes. Mol Cell Biol 22(1):321–331CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Abdellatif M, Packer SE, Michael LH, Zhang D, Charng MJ, Schneider MD (1998) A Ras-dependent pathway regulates RNA polymerase II phosphorylation in cardiac myocytes: implications for cardiac hypertrophy. Mol Cell Biol 18(11):6729–6736CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Sano M, Wang SC, Shirai M, Scaglia F, Xie M, Sakai S, Tanaka T, Kulkarni PA, Barger PM, Youker KA, Taffet GE, Hamamori Y, Michael LH, Craigen WJ, Schneider MD (2004) Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure. EMBO J 23(17):3559–3569.  https://doi.org/10.1038/sj.emboj.7600351 CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Di Micco R, Fontanals-Cirera B, Low V, Ntziachristos P, Yuen SK, Lovell CD, Dolgalev I, Yonekubo Y, Zhang G, Rusinova E, Gerona-Navarro G, Canamero M, Ohlmeyer M, Aifantis I, Zhou MM, Tsirigos A, Hernando E (2014) Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Rep 9(1):234–247.  https://doi.org/10.1016/j.celrep.2014.08.055 CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Winter GE, Mayer A, Buckley DL, Erb MA, Roderick JE, Vittori S, Reyes JM, di Iulio J, Souza A, Ott CJ, Roberts JM, Zeid R, Scott TG, Paulk J, Lachance K, Olson CM, Dastjerdi S, Bauer S, Lin CY, Gray NS, Kelliher MA, Churchman LS, Bradner JE (2017) BET Bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment. Mol Cell 67(1):5–18 e19.  https://doi.org/10.1016/j.molcel.2017.06.004 CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Kaikkonen MU, Spann NJ, Heinz S, Romanoski CE, Allison KA, Stender JD, Chun HB, Tough DF, Prinjha RK, Benner C, Glass CK (2013) Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell 51(3):310–325.  https://doi.org/10.1016/j.molcel.2013.07.010 CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Roder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Falconnet E, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Ruan X, Hayashizaki Y, Harrow J, Gerstein M, Hubbard T, Reymond A, Antonarakis SE, Hannon G, Giddings MC, Ruan Y, Wold B, Carninci P, Guigo R, Gingeras TR (2012) Landscape of transcription in human cells. Nature 489(7414):101–108.  https://doi.org/10.1038/nature11233 CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Buecker C, Wysocka J (2012) Enhancers as information integration hubs in development: lessons from genomics. Trends Genet 28(6):276–284.  https://doi.org/10.1016/j.tig.2012.02.008 CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Azofeifa JG, Allen MA, Hendrix JR, Read T, Rubin JD, Dowell RD (2018) Enhancer RNA profiling predicts transcription factor activity. Genome Res doi: https://doi.org/10.1101/gr.225755.117
  135. 135.
    Banerjee AR, Kim YJ, Kim TH (2014) A novel virus-inducible enhancer of the interferon-beta gene with tightly linked promoter and enhancer activities. Nucleic Acids Res 42(20):12537–12554.  https://doi.org/10.1093/nar/gku1018 CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Hsieh CL, Fei T, Chen Y, Li T, Gao Y, Wang X, Sun T, Sweeney CJ, Lee GS, Chen S, Balk SP, Liu XS, Brown M, Kantoff PW (2014) Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc Natl Acad Sci U S A 111(20):7319–7324.  https://doi.org/10.1073/pnas.1324151111 CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Melo CA, Drost J, Wijchers PJ, van de Werken H, de Wit E, Oude Vrielink JA, Elkon R, Melo SA, Leveille N, Kalluri R, de Laat W, Agami R (2013) eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol Cell 49(3):524–535.  https://doi.org/10.1016/j.molcel.2012.11.021 CrossRefPubMedGoogle Scholar
  138. 138.
    Li W, Notani D, Ma Q, Tanasa B, Nunez E, Chen AY, Merkurjev D, Zhang J, Ohgi K, Song X, Oh S, Kim HS, Glass CK, Rosenfeld MG (2013) Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498(7455):516–520.  https://doi.org/10.1038/nature12210 CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Lai F, Orom UA, Cesaroni M, Beringer M, Taatjes DJ, Blobel GA, Shiekhattar R (2013) Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature 494(7438):497–501.  https://doi.org/10.1038/nature11884 CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Schaukowitch K, Joo JY, Liu X, Watts JK, Martinez C, Kim TK (2014) Enhancer RNA facilitates NELF release from immediate early genes. Mol Cell 56(1):29–42.  https://doi.org/10.1016/j.molcel.2014.08.023 CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Yamaguchi Y, Takagi T, Wada T, Yano K, Furuya A, Sugimoto S, Hasegawa J, Handa H (1999) NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell 97(1):41–51CrossRefPubMedGoogle Scholar
  142. 142.
    Yamaguchi Y, Inukai N, Narita T, Wada T, Handa H (2002) Evidence that negative elongation factor represses transcription elongation through binding to a -inducing factor/RNA polymerase II complex and RNA. Mol Cell Biol 22(9):2918–2927CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Kanno T, Kanno Y, LeRoy G, Campos E, Sun HW, Brooks SR, Vahedi G, Heightman TD, Garcia BA, Reinberg D, Siebenlist U, O’Shea JJ, Ozato K (2014) BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones. Nat Struct Mol Biol 21(12):1047–1057.  https://doi.org/10.1038/nsmb.2912 CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, Hu M, Liu JS, Ren B (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485(7398):376–380.  https://doi.org/10.1038/nature11082 CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Ong CT, Corces VG (2014) CTCF: an architectural protein bridging genome topology and function. Nat Rev Genet 15(4):234–246.  https://doi.org/10.1038/nrg3663 CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Rao SS, Huntley MH, Durand NC, Stamenova EK, Bochkov ID, Robinson JT, Sanborn AL, Machol I, Omer AD, Lander ES, Aiden EL (2014) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159(7):1665–1680.  https://doi.org/10.1016/j.cell.2014.11.021 CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Shen Y, Yue F, McCleary DF, Ye Z, Edsall L, Kuan S, Wagner U, Dixon J, Lee L, Lobanenkov VV, Ren B (2012) A map of the cis-regulatory sequences in the mouse genome. Nature 488(7409):116–120.  https://doi.org/10.1038/nature11243 CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, Amit I, Lajoie BR, Sabo PJ, Dorschner MO, Sandstrom R, Bernstein B, Bender MA, Groudine M, Gnirke A, Stamatoyannopoulos J, Mirny LA, Lander ES, Dekker J (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326(5950):289–293.  https://doi.org/10.1126/science.1181369 CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Gomez-Velazquez M, Badia-Careaga C, Lechuga-Vieco AV, Nieto-Arellano R, Tena JJ, Rollan I, Alvarez A, Torroja C, Caceres EF, Roy AR, Galjart N, Delgado-Olguin P, Sanchez-Cabo F, Enriquez JA, Gomez-Skarmeta JL, Manzanares M (2017) CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart. PLoS Genet 13(8):e1006985.  https://doi.org/10.1371/journal.pgen.1006985 CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Rosa-Garrido M, Chapski DJ, Schmitt AD, Kimball TH, Karbassi E, Monte E, Balderas E, Pellegrini M, Shih TT, Soehalim E, Liem D, Ping P, Galjart NJ, Ren S, Wang Y, Ren B, Vondriska TM (2017) High-resolution mapping of chromatin conformation in cardiac myocytes reveals structural remodeling of the epigenome in heart failure. Circulation 136(17):1613–1625.  https://doi.org/10.1161/CIRCULATIONAHA.117.029430 CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Bonev B, Cavalli G (2016) Organization and function of the 3D genome. Nat Rev Genet 17(12):772.  https://doi.org/10.1038/nrg.2016.147 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Internal Medicine, Division of Cardiovascular Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research CenterUniversity of IowaIowa CityUSA
  2. 2.Department of PharmacologyUniversity of IowaIowa CityUSA

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