MKL1 is an epigenetic modulator of TGF-β induced fibrogenesis

被引：45
作者：
Fan, Zhiwen [1 ]
Hao, Chenzhi [1 ]
Li, Min [1 ]
Dai, Xin [1 ]
Qin, Hao [1 ]
Li, Jianfei [1 ]
Xu, Huihui [1 ]
Wu, Xiaoyan [1 ]
Zhang, Liping [2 ]
Fang, Mingming [1 ,3 ]
Zhou, Bisheng [1 ]
Tian, Wenfang [1 ]
Xu, Yong [1 ]
机构：
[1] Nanjing Med Univ, Dept Pathophysiol, Key Lab Cardiovasc Dis, Nanjing 210029, Jiangsu, Peoples R China
[2] Xinjiang Med Univ, Dept Biochem, Urumqi, Peoples R China
[3] Jiangsu Jiankang Vocat Univ, Dept Nursing, Nanjing, Jiangsu, Peoples R China
来源：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS | 2015年 / 1849卷 / 09期
关键词：
Epigenetics; Transcriptional regulation; Portal fibroblast; Liver fibrosis; TGF-beta; Histone methylation; GROWTH-FACTOR-BETA; PRO-INFLAMMATORY TRANSCRIPTION; PORTAL FIBROBLAST ACTIVATION; RESPONSE FACTOR SRF; MRTF-A; MESENCHYMAL TRANSITION; GENE-EXPRESSION; FIBROSIS; CELLS; SERUM;
D O I：
10.1016/j.bbagrm.2015.07.013
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Transforming growth factor (TGF-beta) induced activation of portal fibroblast cells serves as a primary cause for liver fibrosis following cholestatic injury. The underlying epigenetic mechanism is not clear. We studied the role of a transcriptional modulator, megakaryoblastic leukemia 1 (MKL1) in this process. We report here that Mal deficiency ameliorated BDL-induced liver fibrosis in mice as assessed by histological stainings and expression levels of pro-fibrogenic genes. MKL1 silencing by small interfering RNA (siRNA) abrogated TGF-beta induced transactivation of pro-fibrogenic genes in portal fibroblast cells. TGF-beta stimulated the binding of MKL1 on the promoters of pro-fibrogenic genes and promoted the interaction between MKL1 and SMAD3. While SMAD3 was necessary for MKL1 occupancy on the gene promoters, Mal depletion impaired SMAD3 binding reciprocally. TGF-beta treatment induced the accumulation of trimethylated histone H3K4 on the gene promoters by recruiting a methyltransferase complex. Knockdown of individual members of this complex significantly weakened the binding of SMAD3 and down-regulated the activation of portal fibroblast cells. In conclusion, we have identified an epigenetic pathway that dictates TGF-beta induced pro-fibrogenic transcription in portal fibroblast thereby providing novel insights for the development of therapeutic solutions to treat liver fibrosis. (C) 2015 Elsevier B.V. All rights reserved.
引用
收藏
页码：1219 / 1228
页数：10
相关论文
共 53 条
  • [1] Transforming growth factor β and the liver
    Bissell, DM
    Roulot, D
    George, J
    [J]. HEPATOLOGY, 2001, 34 (05) : 859 - 867
  • [2] The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-β signaling
    Borkham-Kamphorst, Erawan
    Schaffrath, Christian
    Van de Leur, Eddy
    Haas, Ute
    Tihaa, Lidia
    Meurer, Steffen K.
    Nevzorova, Yulia A.
    Liedtke, Christian
    Weiskirchen, Ralf
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2014, 1843 (05): : 902 - 914
  • [3] Next-generation sequencing identifies TGF-β1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy
    Brennan, Eoin P.
    Morine, Melissa J.
    Walsh, David W.
    Roxburgh, Sarah A.
    Lindenmeyer, Maja T.
    Brazil, Derek P.
    Gaora, Peadar O.
    Roche, Helen M.
    Sadlier, Denise M.
    Cohen, Clemens D.
    Godson, Catherine
    Martin, Finian
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 2012, 1822 (04): : 589 - 599
  • [4] Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes
    Cen, B
    Selvaraj, A
    Burgess, RC
    Hitzler, JK
    Ma, ZG
    Morris, SW
    Prywes, R
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (18) : 6597 - 6608
  • [5] Megakaryocytic Leukemia 1 Directs a Histone H3 Lysine 4 Methyltransferase Complex to Regulate Hypoxic Pulmonary Hypertension
    Chen, Dewei
    Yang, Yuyu
    Cheng, Xian
    Fang, Fei
    Xu, Gang
    Yuan, Zhibin
    Xia, Jun
    Kong, Hui
    Xie, Weiping
    Wang, Hong
    Fang, Mingming
    Gao, Yuqi
    Xu, Yong
    [J]. HYPERTENSION, 2015, 65 (04) : 821 - +
  • [6] Cheng X., 2015, ONCOGENE
  • [7] Lineage Tracing Demonstrates No Evidence of Cholangiocyte Epithelial-to-Mesenchymal Transition in Murine Models of Hepatic Fibrosis
    Chu, Andrew S.
    Diaz, Rosalyn
    Hui, Jia-Ji
    Yanger, Kilangsungla
    Zong, Yiwei
    Alpini, Gianfranco
    Stanger, Ben Z.
    Wells, Rebecca G.
    [J]. HEPATOLOGY, 2011, 53 (05) : 1685 - 1695
  • [8] Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices
    Clouzeau-Girard, H
    Guyot, C
    Combe, C
    Moronvalle-Halley, V
    Housset, C
    Lamireau, T
    Rosenbaum, J
    Desmoulière, A
    [J]. LABORATORY INVESTIGATION, 2006, 86 (03) : 275 - 285
  • [9] Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-β-dependent mechanisms
    Copple, Bryan L.
    [J]. LIVER INTERNATIONAL, 2010, 30 (05) : 669 - 682
  • [10] SMAD3 and SP1/SP3 Transcription Factors Collaborate to Regulate Connective Tissue Growth Factor Gene Expression in Myoblasts in Response to Transforming Growth Factor
    Cordova, Gonzalo
    Rochard, Alice
    Riquelme-Guzman, Camilo
    Cofre, Catalina
    Scherman, Daniel
    Bigey, Pascal
    Brandan, Enrique
    [J]. JOURNAL OF CELLULAR BIOCHEMISTRY, 2015, 116 (09) : 1880 - 1887
123456