Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis

被引：83

作者：

Dufton, Neil P. ^{[1
]}

Peghaire, Claire R. ^{[1
]}

Osuna-Almagro, Lourdes ^{[1
]}

Raimondi, Claudio ^{[1
]}

Kalna, Viktoria ^{[1
]}

Chuahan, Abhishek ^{[2
]}

Webb, Gwilym ^{[2
]}

Yang, Youwen ^{[1
]}

Birdsey, Graeme M. ^{[1
]}

Lalor, Patricia ^{[2
]}

Mason, Justin C. ^{[1
]}

Adams, David H. ^{[2
]}

Randi, Anna M. ^{[1
]}

机构：

[1] Imperial Coll London, Vasc Sci, Imperial Ctr Translat & Expt Med, Natl Heart & Lung Inst, London W12 0NN, England

[2] Univ Birmingham, Liver Res Ctr, Inst Biomed Res, Inst Immunol & Immunotherapy,Coll Med & Dent Sci, Birmingham B15 2TT, W Midlands, England

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

TO-MESENCHYMAL TRANSITION; PULMONARY-HYPERTENSION; CELLS; ACTIVATION; EXPRESSION; CIRRHOSIS; TRANSFORMATION; PROMOTER;

D O I：

10.1038/s41467-017-01169-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The role of the endothelium in protecting from chronic liver disease and TGF beta-mediated fibrosis remains unclear. Here we describe how the endothelial transcription factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGF beta-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (Erg(cEC-Het)) and inducible homozygous deficient mice (Erg(iEC-KO)), in a SMAD3-dependent manner. Acute administration of the TNF-alpha inhibitor etanercept inhibits carbon tetrachloride (CCL4)-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease.

引用

页数：14

共 45 条

[1] The Endothelial Transcription Factor ERG Promotes Vascular Stability and Growth through Wnt/β-Catenin Signaling [J].

Birdsey, Graeme M. ;

Shah, Aarti V. ;

Dufton, Neil ;

Reynolds, Louise E. ;

Almagro, Lourdes Osuna ;

Yang, Youwen ;

Aspalter, Irene M. ;

Khan, Samia T. ;

Mason, Justin C. ;

Dejana, Elisabetta ;

Goettgens, Berthold ;

Hodivala-Dilke, Kairbaan ;

Gerhardt, Holger ;

Adams, Ralf H. ;

Randi, Anna M. .

DEVELOPMENTAL CELL, 2015, 32 (01) :82-96

[2] The transcription factor Erg regulates expression of histone deacetylase 6 and multiple pathways involved in endothelial cell migration and angiogenesis [J].

Birdsey, Graeme M. ;

Dryden, Nicola H. ;

Shah, Aarti V. ;

Hannah, Rebecca ;

Hall, Matthew D. ;

Haskard, Dorian O. ;

Parsons, Maddy ;

Mason, Justin C. ;

Zvelebil, Marketa ;

Gottgens, Berthold ;

Ridley, Anne J. ;

Randi, Anna M. .

BLOOD, 2012, 119 (03) :894-903

[3] Endothelial-to-mesenchymal transition drives atherosclerosis progression [J].

Chen, Pei-Yu ;

Qin, Lingfeng ;

Baeyens, Nicolas ;

Li, Guangxin ;

Afolabi, Titilayo ;

Budatha, Madhusudhan ;

Tellides, George ;

Schwartz, Martin A. ;

Simons, Michael .

JOURNAL OF CLINICAL INVESTIGATION, 2015, 125 (12) :4514-4528

[4] FGF Regulates TGF-β Signaling and Endothelial-to-Mesenchymal Transition via Control of let-7 miRNA Expression [J].

Chen, Pei-Yu ;

Qin, Lingfeng ;

Barnes, Carmen ;

Charisse, Klaus ;

Yi, Tai ;

Zhang, Xinbo ;

Ali, Rahmat ;

Medina, Pedro P. ;

Yu, Jun ;

Slack, Frank J. ;

Anderson, Daniel G. ;

Kotelianski, Victor ;

Wang, Fen ;

Tellides, George ;

Simons, Michael .

CELL REPORTS, 2012, 2 (06) :1684-1696

[5]

Chen WX, 2002, WORLD J GASTROENTERO, V8, P379

[6] TGF-β Signaling Mediates Endothelial-to-Mesenchymal Transition (EndMT) During Vein Graft Remodeling [J].

Cooley, Brian C. ;

Nevado, Jose ;

Mellad, Jason ;

Yang, Dan ;

St Hilaire, Cynthia ;

Negro, Alejandra ;

Fang, Fang ;

Chen, Guibin ;

San, Hong ;

Walts, Avram D. ;

Schwartzbeck, Robin L. ;

Taylor, Brandi ;

Lanzer, Jan D. ;

Wragg, Andrew ;

Elagha, Abdalla ;

Beltran, Leilani E. ;

Berry, Colin ;

Feil, Robert ;

Virmani, Renu ;

Ladich, Elena ;

Kovacic, Jason C. ;

Boehm, Manfred .

SCIENCE TRANSLATIONAL MEDICINE, 2014, 6 (227)

[7] Erg cooperates with TGF-β to control mesenchymal differentiation [J].

Cox, Megan K. ;

Appelboom, Brittany L. ;

Ban, Ga I. ;

Serra, Rosa .

EXPERIMENTAL CELL RESEARCH, 2014, 328 (02) :410-418

[8]

Craig R., 2008, Health Survey for England 2006, Volume 1: Cardiovascular disease and risk factors in adults

[9] Liver sinusoidal endothelial cells and liver regeneration [J].

DeLeve, Laurie D. .

JOURNAL OF CLINICAL INVESTIGATION, 2013, 123 (05) :1861-1866

[10] Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis [J].

Ding, Bi-Sen ;

Cao, Zhongwei ;

Lis, Raphael ;

Nolan, Daniel J. ;

Guo, Peipei ;

Simons, Michael ;

Penfold, Mark E. ;

Shido, Koji ;

Rabbany, Sina Y. ;

Rafii, Shahin .

NATURE, 2014, 505 (7481) :97-+

← 1 2 3 4 5 →