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

页码：1219 / 1228

页数：10

共 53 条

[1] Transforming growth factor β and the liver [J].

Bissell, DM ;

Roulot, D ;

George, 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 [J].

Borkham-Kamphorst, Erawan ;

Schaffrath, Christian ;

Van de Leur, Eddy ;

Haas, Ute ;

Tihaa, Lidia ;

Meurer, Steffen K. ;

Nevzorova, Yulia A. ;

Liedtke, Christian ;

Weiskirchen, Ralf .

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 [J].

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 .

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 [J].

Cen, B ;

Selvaraj, A ;

Burgess, RC ;

Hitzler, JK ;

Ma, ZG ;

Morris, SW ;

Prywes, R .

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 [J].

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 .

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 [J].

Chu, Andrew S. ;

Diaz, Rosalyn ;

Hui, Jia-Ji ;

Yanger, Kilangsungla ;

Zong, Yiwei ;

Alpini, Gianfranco ;

Stanger, Ben Z. ;

Wells, Rebecca G. .

HEPATOLOGY, 2011, 53 (05) :1685-1695

[8] Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices [J].

Clouzeau-Girard, H ;

Guyot, C ;

Combe, C ;

Moronvalle-Halley, V ;

Housset, C ;

Lamireau, T ;

Rosenbaum, J ;

Desmoulière, A .

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 [J].

Copple, Bryan L. .

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 [J].

Cordova, Gonzalo ;

Rochard, Alice ;

Riquelme-Guzman, Camilo ;

Cofre, Catalina ;

Scherman, Daniel ;

Bigey, Pascal ;

Brandan, Enrique .

JOURNAL OF CELLULAR BIOCHEMISTRY, 2015, 116 (09) :1880-1887

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