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Epigenetic Mechanisms of Pancreatobiliary Fibrosis

  • Sayed Obaidullah Aseem
  • Robert C. HuebertEmail author
Pancreas (V Chandrasekhara, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Pancreas

Abstract

Purpose of review

The goal of this manuscript is to review the current literature related to fibrogenesis in the pancreatobiliary system and how this process contributes to pancreatic and biliary diseases. In particular, we seek to define the current state of knowledge regarding the epigenetic mechanisms that govern and regulate tissue fibrosis in these organs. A better understanding of these underlying molecular events will set the stage for future epigenetic therapeutics.

Recent findings

We highlight the significant advances that have been made in defining the pathogenesis of pancreatobiliary fibrosis as it relates to chronic pancreatitis, pancreatic cancer, and the fibro-obliterative cholangiopathies. We also review the cell types involved as well as concepts related to epithelial-mesenchymal crosstalk. Furthermore, we outline important signaling pathways (e.g., TGFβ) and diverse epigenetic processes (i.e., DNA methylation, non-coding RNAs, histone modifications, and 3D chromatin remodeling) that regulate fibrogenic gene networks in these conditions.

Summary

We review a growing body of scientific evidence linking epigenetic regulatory events to fibrotic disease states in the pancreas and biliary system. Advances in this understudied area will be critical toward developing epigenetic pharmacological approaches that may lead to more effective treatments for these devastating and difficult to treat disorders.

Keywords

Pancreas Biliary Pancreatic stellate cell Cholangiocytes Epigenetics Fibrosis 

Notes

Acknowledgments

The authors acknowledge Lyndsay M. Busby for her secretarial support.

Funding

This work was supported by grants DK100575, DK113339, DK117861 and from the National Institutes of Health.

Compliance with ethical standards

Conflict of interest

Sayed Obaidullah Aseem and Robert C. Huebert declare that they have no conflict of interest.

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    • Kleeff J, Whitcomb DC, Shimosegawa T, Esposito I, Lerch MM, Gress T, et al. Chronic pancreatitis. Nat Rev Dis Primers. 2017;3:17060 This article provides a comprehensive review of chronic pancreatitis, its epidemiology, pathophysiology, diagnosis, and management.Google Scholar
  2. 2.
    Cote GA, Yadav D, Slivka A, Hawes RH, Anderson MA, Burton FR, et al. Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis. Clin Gastroenterol Hepatol. 2011;9(3):266–73 quiz e27.Google Scholar
  3. 3.
    Conwell DL, Banks PA, Sandhu BS, Sherman S, Al-Kaade S, Gardner TB, et al. Validation of demographics, etiology, and risk factors for chronic pancreatitis in the USA: a report of the North American Pancreas Study (NAPS) Group. Dig Dis Sci. 2017;62(8):2133–40.Google Scholar
  4. 4.
    Lee E, Ryu GR, Ko SH, Ahn YB, Song KH. A role of pancreatic stellate cells in islet fibrosis and beta-cell dysfunction in type 2 diabetes mellitus. Biochem Biophys Res Commun. 2017;485(2):328–34.Google Scholar
  5. 5.
    Whatcott CJ, Diep CH, Jiang P, Watanabe A, LoBello J, Sima C, et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res. 2015;21(15):3561–8.Google Scholar
  6. 6.
    • Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, et al. Stromal biology and therapy in pancreatic cancer. Gut. 2011;60(6):861–8 This review provides a thorough discussion of the role of dysmoplasia, stroma microenvironment, and contribution of PSCs to these processes in pancreatic cancer.Google Scholar
  7. 7.
    Kanat O, Ertas H. Shattering the castle walls: anti-stromal therapy for pancreatic cancer. World J Gastrointest Oncol. 2018;10(8):202–10.Google Scholar
  8. 8.
    Kota J, Hancock J, Kwon J, Korc M. Pancreatic cancer: stroma and its current and emerging targeted therapies. Cancer Lett. 2017;391:38–49.Google Scholar
  9. 9.
    Ikenaga N, Ohuchida K, Mizumoto K, Cui L, Kayashima T, Morimatsu K, et al. CD10+ pancreatic stellate cells enhance the progression of pancreatic cancer. Gastroenterology. 2010;139(3):1041–51, 51 e1–8.Google Scholar
  10. 10.
    Birtolo C, Pham H, Morvaridi S, Chheda C, Go VL, Ptasznik A, et al. Cadherin-11 is a cell surface marker up-regulated in activated pancreatic stellate cells and is involved in pancreatic cancer cell migration. Am J Pathol. 2017;187(1):146–55.Google Scholar
  11. 11.
    Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998;43(1):128–33.Google Scholar
  12. 12.
    Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115(2):421–32.Google Scholar
  13. 13.
    Buchholz M, Kestler HA, Holzmann K, Ellenrieder V, Schneiderhan W, Siech M, et al. Transcriptome analysis of human hepatic and pancreatic stellate cells: organ-specific variations of a common transcriptional phenotype. J Mol Med (Berl). 2005;83(10):795–805.Google Scholar
  14. 14.
    Allam A, Thomsen AR, Gothwal M, Saha D, Maurer J, Brunner TB. Pancreatic stellate cells in pancreatic cancer: in focus. Pancreatology. 2017;17(4):514–22.Google Scholar
  15. 15.
    Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol. 2012;3:344.Google Scholar
  16. 16.
    Apte M, Pirola RC, Wilson JS. Pancreatic stellate cell: physiologic role, role in fibrosis and cancer. Curr Opin Gastroenterol. 2015;31(5):416–23.Google Scholar
  17. 17.
    Vonlaufen A, Xu Z, Daniel B, Kumar RK, Pirola R, Wilson J, et al. Bacterial endotoxin: a trigger factor for alcoholic pancreatitis? Evidence from a novel, physiologically relevant animal model. Gastroenterology. 2007;133(4):1293–303.Google Scholar
  18. 18.
    Masamune A, Kikuta K, Watanabe T, Satoh K, Satoh A, Shimosegawa T. Pancreatic stellate cells express Toll-like receptors. J Gastroenterol. 2008;43(5):352–62.Google Scholar
  19. 19.
    Schneider E, Schmid-Kotsas A, Zhao J, Weidenbach H, Schmid RM, Menke A, et al. Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells. Am J Physiol Cell Physiol. 2001;281(2):C532–43.Google Scholar
  20. 20.
    Mews P, Phillips P, Fahmy R, Korsten M, Pirola R, Wilson J, et al. Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis. Gut. 2002;50(4):535–41.Google Scholar
  21. 21.
    Apte MV, Haber PS, Darby SJ, Rodgers SC, McCaughan GW, Korsten MA, et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut. 1999;44(4):534–41.Google Scholar
  22. 22.
    Ohnishi H, Miyata T, Yasuda H, Satoh Y, Hanatsuka K, Kita H, et al. Distinct roles of Smad2-, Smad3-, and ERK-dependent pathways in transforming growth factor-beta1 regulation of pancreatic stellate cellular functions. J Biol Chem. 2004;279(10):8873–8.Google Scholar
  23. 23.
    Haber PS, Keogh GW, Apte MV, Moran CS, Stewart NL, Crawford DH, et al. Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis. Am J Pathol. 1999;155(4):1087–95.Google Scholar
  24. 24.
    Pang TCY, Wilson JS, Apte MV. Pancreatic stellate cells: what’s new? Curr Opin Gastroenterol. 2017;33(5):366–73.Google Scholar
  25. 25.
    Xiao W, Jiang W, Shen J, Yin G, Fan Y, Wu D, et al. Retinoic acid ameliorates pancreatic fibrosis and inhibits the activation of pancreatic stellate cells in mice with experimental chronic pancreatitis via suppressing the Wnt/beta-catenin signaling pathway. PLoS One. 2015;10(11):e0141462.Google Scholar
  26. 26.
    Xu M, Cai J, Wei H, Zhou M, Xu P, Huang H, et al. Scoparone protects against pancreatic fibrosis via TGF-beta/Smad signaling in rats. Cell Physiol Biochem. 2016;40(1–2):277–86.Google Scholar
  27. 27.
    Jaster R, Lichte P, Fitzner B, Brock P, Glass A, Karopka T, et al. Peroxisome proliferator-activated receptor gamma overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells. J Cell Mol Med. 2005;9(3):670–82.Google Scholar
  28. 28.
    Hisada S, Shimizu K, Shiratori K, Kobayashi M. Peroxisome proliferator-activated receptor gamma ligand prevents the development of chronic pancreatitis through modulating NF-kappaB-dependent proinflammatory cytokine production and pancreatic stellate cell activation. Rocz Akad Med Bialymst. 2005;50:142–7.Google Scholar
  29. 29.
    Phillips PA, McCarroll JA, Park S, Wu MJ, Pirola R, Korsten M, et al. Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover. Gut. 2003;52(2):275–82.Google Scholar
  30. 30.
    • Chronopoulos A, Robinson B, Sarper M, Cortes E, Auernheimer V, Lachowski D, et al. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion. Nat Commun. 2016;7:12630 Provides mechanistic understanding of the role of PSCs in pancreatic cancer metastasis.Google Scholar
  31. 31.
    Lazaridis KN, Strazzabosco M, Larusso NF. The cholangiopathies: disorders of biliary epithelia. Gastroenterology. 2004 Nov;127(5):1565–77.Google Scholar
  32. 32.
    •• Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol. 2019 May;16(5):269–281This review provides a comprehensive overview of cholangiocyte biology in health and disease. Mechanisms and signaling pathways involved in biliary disease are discussed.Google Scholar
  33. 33.
    Santos-Laso A, Munoz-Garrido P, Felipe-Agirre M, Bujanda L, Banales JM, Perugorria MJ. New advances in the molecular mechanisms driving biliary fibrosis and emerging molecular targets. Curr Drug Targets. 2017;18(8):908–20.Google Scholar
  34. 34.
    Pinto C, Giordano DM, Maroni L, Marzioni M. Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4 Pt B):1270–8.Google Scholar
  35. 35.
    • Iwaisako K, Jiang C, Zhang M, Cong M, Moore-Morris TJ, Park TJ, et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci U S A. 2014;111(32):E3297–305 This study shows the contribution of portal fibroblasts and HSCs to the myofibroblast pool and consequently hepatobiliary fibrosis.Google Scholar
  36. 36.
    Lemoinne S, Cadoret A, El Mourabit H, Thabut D, Housset C. Origins and functions of liver myofibroblasts. Biochim Biophys Acta. 2013 Jul;1832(7):948–54.Google Scholar
  37. 37.
    Dranoff JA, Wells RG. Portal fibroblasts: underappreciated mediators of biliary fibrosis. Hepatology. 2010 Apr;51(4):1438–44.Google Scholar
  38. 38.
    Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, et al. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest. 2008;118(10):3331–42.Google Scholar
  39. 39.
    Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun. 2013;4:2823.Google Scholar
  40. 40.
    Wake K. "Sternzellen" in the liver: perisinusoidal cells with special reference to storage of vitamin A. Am J Anat. 1971;132(4):429–62.Google Scholar
  41. 41.
    • Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14(7):397–411 A comprehensive overview of the mechanisms of HSC activation.Google Scholar
  42. 42.
    Kocabayoglu P, Lade A, Lee YA, Dragomir AC, Sun X, Fiel MI, et al. Beta-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J Hepatol. 2015;63(1):141–7.Google Scholar
  43. 43.
    Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, et al. Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med. 2013;19(12):1617–24.Google Scholar
  44. 44.
    Michelotti GA, Xie G, Swiderska M, Choi SS, Karaca G, Kruger L, et al. Smoothened is a master regulator of adult liver repair. J Clin Invest. 2013;123(6):2380–94.Google Scholar
  45. 45.
    Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12(6):325–38.Google Scholar
  46. 46.
    Zhou Q, Xia S, Guo F, Hu F, Wang Z, Ni Y, et al. Transforming growth factor-beta in pancreatic diseases: mechanisms and therapeutic potential. Pharmacol Res. 2019;142:58–69.Google Scholar
  47. 47.
    Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009;19(1):128–39.Google Scholar
  48. 48.
    Pujadas E, Feinberg AP. Regulated noise in the epigenetic landscape of development and disease. Cell. 2012;148(6):1123–31.Google Scholar
  49. 49.
    Lin JC, Jeong S, Liang G, Takai D, Fatemi M, Tsai YC, et al. Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island. Cancer Cell. 2007;12(5):432–44.Google Scholar
  50. 50.
    Holmgren C, Kanduri C, Dell G, Ward A, Mukhopadhya R, Kanduri M, et al. CpG methylation regulates the Igf2/H19 insulator. Curr Biol. 2001;11(14):1128–30.Google Scholar
  51. 51.
    Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333(6047):1300–3.Google Scholar
  52. 52.
    Koch A, Joosten SC, Feng Z, de Ruijter TC, Draht MX, Melotte V, et al. Analysis of DNA methylation in cancer: location revisited. Nat Rev Clin Oncol. 2018;15(7):459–66.Google Scholar
  53. 53.
    Lomberk GA, Iovanna J, Urrutia R. The promise of epigenomic therapeutics in pancreatic cancer. Epigenomics. 2016;8(6):831–42.Google Scholar
  54. 54.
    Mishra NK, Guda C. Genome-wide DNA methylation analysis reveals molecular subtypes of pancreatic cancer. Oncotarget. 2017;8(17):28990–9012.Google Scholar
  55. 55.
    McCleary-Wheeler AL, Lomberk GA, Weiss FU, Schneider G, Fabbri M, Poshusta TL, et al. Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. Cancer Lett. 2013;328(2):212–21.Google Scholar
  56. 56.
    Dutruel C, Bergmann F, Rooman I, Zucknick M, Weichenhan D, Geiselhart L, et al. Early epigenetic downregulation of WNK2 kinase during pancreatic ductal adenocarcinoma development. Oncogene. 2014;33(26):3401–10.Google Scholar
  57. 57.
    El Taghdouini A, Sorensen AL, Reiner AH, Coll M, Verhulst S, Mannaerts I, et al. Genome-wide analysis of DNA methylation and gene expression patterns in purified, uncultured human liver cells and activated hepatic stellate cells. Oncotarget. 2015;6(29):26729–45.Google Scholar
  58. 58.
    Mann J, Chu DC, Maxwell A, Oakley F, Zhu NL, Tsukamoto H, et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology. 2010;138(2):705–14, 14 e1–4.Google Scholar
  59. 59.
    Perugorria MJ, Wilson CL, Zeybel M, Walsh M, Amin S, Robinson S, et al. Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. Hepatology. 2012;56(3):1129–39.Google Scholar
  60. 60.
    Page A, Paoli P, Moran Salvador E, White S, French J, Mann J. Hepatic stellate cell transdifferentiation involves genome-wide remodeling of the DNA methylation landscape. J Hepatol. 2016;64(3):661–73.Google Scholar
  61. 61.
    Patil VS, Zhou R, Rana TM. Gene regulation by non-coding RNAs. Crit Rev Biochem Mol Biol. 2014;49(1):16–32.Google Scholar
  62. 62.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.Google Scholar
  63. 63.
    Massey V, Cabezas J, Bataller R. Epigenetics in liver fibrosis. Semin Liver Dis. 2017;37(3):219–30.Google Scholar
  64. 64.
    El Taghdouini A, van Grunsven LA. Epigenetic regulation of hepatic stellate cell activation and liver fibrosis. Expert Rev Gastroenterol Hepatol. 2016;10(12):1397–408.Google Scholar
  65. 65.
    Lin YC, Wang FS, Yang YL, Chuang YT, Huang YH. MicroRNA-29a mitigation of toll-like receptor 2 and 4 signaling and alleviation of obstructive jaundice-induced fibrosis in mice. Biochem Biophys Res Commun. 2018;496(3):880–6.Google Scholar
  66. 66.
    Zhao R, Dong R, Yang Y, Wang Y, Ma J, Wang J, et al. MicroRNA-155 modulates bile duct inflammation by targeting the suppressor of cytokine signaling 1 in biliary atresia. Pediatr Res. 2017;82(6):1007–16.Google Scholar
  67. 67.
    Yu P, Liu K, Gao X, Karmouty-Quintana H, Bailey JM, Cao Y, et al. Transforming growth factor-beta and bone morphogenetic protein 2 regulation of microRNA-200 family in chronic pancreatitis. Pancreas. 2018;47(2):252–6.Google Scholar
  68. 68.
    Xu M, Wang G, Zhou H, Cai J, Li P, Zhou M, et al. TGF-beta1-miR-200a-PTEN induces epithelial-mesenchymal transition and fibrosis of pancreatic stellate cells. Mol Cell Biochem. 2017;431(1–2):161–8.Google Scholar
  69. 69.
    Masamune A, Nakano E, Hamada S, Takikawa T, Yoshida N, Shimosegawa T. Alteration of the microRNA expression profile during the activation of pancreatic stellate cells. Scand J Gastroenterol. 2014;49(3):323–31.Google Scholar
  70. 70.
    Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43(6):904–14.Google Scholar
  71. 71.
    Liu H, Yu K, Ma P, Xiong L, Wang M, Wang W. Long noncoding RNA myocardial infarction-associated transcript regulated the pancreatic stellate cell activation to promote the fibrosis process of chronic pancreatitis. J Cell Biochem. 2019 Jun;120(6):9547–9555.Google Scholar
  72. 72.
    Wang H, Jiang Y, Lu M, Sun B, Qiao X, Xue D, et al. STX12 lncRNA/miR-148a/SMAD5 participate in the regulation of pancreatic stellate cell activation through a mechanism involving competing endogenous RNA. Pancreatology. 2017;17(2):237–46.Google Scholar
  73. 73.
    Thankam FG, Boosani CS, Dilisio MF, Agrawal DK. Epigenetic mechanisms and implications in tendon inflammation (review). Int J Mol Med. 2019;43(1):3–14.Google Scholar
  74. 74.
    Feinberg AP. The key role of epigenetics in human disease prevention and mitigation. N Engl J Med. 2018;378(14):1323–34.Google Scholar
  75. 75.
    Zhang G, Pradhan S. Mammalian epigenetic mechanisms. IUBMB Life. 2014;66(4):240–56.Google Scholar
  76. 76.
    Taniguchi Y. The Bromodomain and extra-terminal domain (BET) family: functional anatomy of BET paralogous proteins. Int J Mol Sci. 2016;7:17(11).Google Scholar
  77. 77.
    • Bombardo M, Chen R, Malagola E, Saponara E, Hills AP, Graf R, et al. Inhibition of class I histone deacetylases abrogates tumor growth factor beta expression and development of fibrosis during chronic pancreatitis. Mol Pharmacol. 2018;94(2):793–801 This study describes an epigenetic mechanism for fibrosis in chronic pancreatitis.Google Scholar
  78. 78.
    Pan MR, Hsu MC, Luo CW, Chen LT, Shan YS, Hung WC. The histone methyltransferase G9a as a therapeutic target to override gemcitabine resistance in pancreatic cancer. Oncotarget. 2016;7(38):61136–51.Google Scholar
  79. 79.
    Kim JS, Shukla SD. Histone h3 modifications in rat hepatic stellate cells by ethanol. Alcohol Alcohol. 2005;40(5):367–72.Google Scholar
  80. 80.
    Mannaerts I, Nuytten NR, Rogiers V, Vanderkerken K, van Grunsven LA, Geerts A. Chronic administration of valproic acid inhibits activation of mouse hepatic stellate cells in vitro and in vivo. Hepatology. 2010;51(2):603–14.Google Scholar
  81. 81.
    Moran-Salvador E, Mann J. Epigenetics and liver fibrosis. Cell Mol Gastroenterol Hepatol. 2017;4(1):125–34.Google Scholar
  82. 82.
    Martin-Mateos R, De Assuncao TM, Arab JP, Jalan-Sakrikar N, Yaqoob U, Greuter T, et al. Enhancer of zeste homologue 2 inhibition attenuates TGF-beta dependent hepatic stellate cell activation and liver fibrosis. Cell Mol Gastroenterol Hepatol. 2019;7(1):197–209.Google Scholar
  83. 83.
    Page A, Paoli PP, Hill SJ, Howarth R, Wu R, Kweon SM, et al. Alcohol directly stimulates epigenetic modifications in hepatic stellate cells. J Hepatol. 2015 Feb;62(2):388–97.Google Scholar
  84. 84.
    Dou C, Liu Z, Tu K, Zhang H, Chen C, Yaqoob U, et al. P300 acetyltransferase mediates stiffness-induced activation of hepatic stellate cells into tumor-promoting myofibroblasts. Gastroenterology. 2018;154(8):2209–21 e14.Google Scholar
  85. 85.
    Ding N, Hah N, Yu RT, Sherman MH, Benner C, Leblanc M, et al. BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A. 2015;112(51):15713–8.Google Scholar
  86. 86.
    • Jalan-Sakrikar N, De Assuncao TM, Shi G, Aseem SO, Chi C, Shah VH, Huebert RC. Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis. Hepatology. 2019 May 9.  https://doi.org/10.1002/hep.30706Describes a role for H3K27me3 and the methyltransferase EZH2 in biliary fibrosis.
  87. 87.
    Harr JC, Luperchio TR, Wong X, Cohen E, Wheelan SJ, Reddy KL. Directed targeting of chromatin to the nuclear lamina is mediated by chromatin state and A-type lamins. J Cell Biol. 2015;208(1):33–52.Google Scholar
  88. 88.
    Lupianez DG, Kraft K, Heinrich V, Krawitz P, Brancati F, Klopocki E, et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell. 2015;161(5):1012–25.Google Scholar
  89. 89.
    Hamdan FH, Johnsen SA. Super enhancers - new analyses and perspectives on the low hanging fruit. Transcription. 2018;9(2):123–30.Google Scholar
  90. 90.
    Hamdan FH, Johnsen SA. DeltaNp63-dependent super enhancers define molecular identity in pancreatic cancer by an interconnected transcription factor network. Proc Natl Acad Sci U S A. 2018;115(52):E12343–E52.Google Scholar
  91. 91.
    Struhl K, Segal E. Determinants of nucleosome positioning. Nat Struct Mol Biol. 2013;20(3):267–73.Google Scholar
  92. 92.
    Ribeiro-Silva C, Vermeulen W, Lans H. SWI/SNF: complex complexes in genome stability and cancer. DNA Repair (Amst). 2019;77:87–95.Google Scholar
  93. 93.
    Li H, Lan J, Han C, Guo K, Wang G, Hu J, et al. Brg1 promotes liver fibrosis via activation of hepatic stellate cells. Exp Cell Res. 2018;364(2):191–7.Google Scholar
  94. 94.
    Esvelt KM, Wang HH. Genome-scale engineering for systems and synthetic biology. Mol Syst Biol. 2013;9:641.Google Scholar

Copyright information

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

Authors and Affiliations

  • Sayed Obaidullah Aseem
    • 1
    • 2
  • Robert C. Huebert
    • 1
    • 2
    • 3
    Email author
  1. 1.Division of Gastroenterology and HepatologyRochesterUSA
  2. 2.Gastroenterology Research UnitMayo ClinicRochesterUSA
  3. 3.Mayo Clinic FoundationRochesterUSA

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