Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis

Xie, Ting; Liang, Jiurong; Liu, Ningshan; Huan, Caijuan; Zhang, Yanli; Liu, Weijia; Kumar, Maya; Xiao, Rui; DʼArmiento, Jeanine; Metzger, Daniel; Chambon, Pierre; Papaioannou, Virginia E.; Stripp, Barry R.; Jiang, Dianhua; Noble, Paul W.

doi:10.1172/jci85328

Cited by 118 publications

(121 citation statements)

References 74 publications

(108 reference statements)

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“…T-box genes are transcription factors known to be involved in several developmental and cardiovascular diseases [44]. Recently, TBX4 was found to play an important role in lung fibrosis in mice via its actions in αSMA+ myofibroblasts and COL1α1+ fibroblasts [45]. Consistent with its role in fibrosis, we found that TBX4 knockdown decreased COL1A1 , COL3A1 , and LOX expression (Figure 4).…”

Section: Discussionsupporting

confidence: 79%

Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop

Bertero

Handen

Chan

2018

IJMS

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Pulmonary arterial hypertension (PAH) is characterized by occlusion of lung arterioles, leading to marked increases in pulmonary vascular resistance. Although heritable forms of PAH are known to be driven by genetic mutations that share some commonality of function, the extent to which these effectors converge to regulate shared processes in this disease is unknown. We have causally connected extracellular matrix (ECM) remodeling and mechanotransduction to the miR-130/301 family in a feedback loop that drives vascular activation and downstream PAH. However, the molecular interconnections between factors genetically associated with PAH and this mechano-driven feedback loop remain undefined. We performed systematic manipulation of matrix stiffness, the miR-130/301 family, and factors genetically associated with PAH in primary human pulmonary arterial cells and assessed downstream and reciprocal consequences on their expression. We found that a network of factors linked to heritable PAH converges upon the matrix stiffening-miR-130/301-PPARγ-LRP8 axis in order to remodel the ECM. Furthermore, we leveraged a computational network biology approach to predict a number of additional molecular circuits functionally linking this axis to the ECM. These results demonstrate that multiple genes associated with heritable PAH converge to control the miR-130/301 circuit, triggering a self-amplifying feedback process central to pulmonary vascular stiffening and disease.

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Section: Discussionsupporting

confidence: 79%

Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop

Bertero

Handen

Chan

2018

IJMS

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“…Its postnatal deletion from cardiomyocytes led to cardiac fibrosis (36), while on the other hand, its deletion from alveolar epithelial cells protected against radiationinduced pulmonary fibrosis and epithelial-mesenchymal transition (EMT) (37). Recent studies using lineage tracing to explore the origins of myofibroblasts -the ultimate effectors of tissue fibrosis -in models of lung fibrosis have concluded that an in vivo role for EMT is either absent or minimal (38)(39)(40) and instead emphasize the importance of resident lung fibroblasts as their major source (39,40). Despite this, FOXM1 has never previously been interrogated in fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…Although this is a limitation of the specificity of a Col1a2-driven Cre system to delete FOXM1 from fibroblasts, no gene is currently recognized as being superior to Col1 for its ability to specifically distinguish fibroblasts from other cell types in a fibrotic milieu. Furthermore, lineagetracing studies strongly suggest that resident fibroblasts are the predominant source of Col1 expression and of myofibroblasts in bleomycin-induced lung fibrosis (40). Therefore, we utilized inducible Col1a2 promoter-driven expression of Cre recombinase in FOXM1 fl/fl mice (conditional FOXM1-knockout mice) and suggest that use of the Col1a2-driven Cre system represents the best available approach to understanding the contribution of a fibroblast-specific gene.…”

Section: Discussionmentioning

confidence: 99%

FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

Penke

Speth

Dommeti

et al. 2018

Journal of Clinical Investigation

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“…Cre ; Sin3a flox/+ ; Rosa26-mT/mG mice were generated by crossing Tbx4 Cre mice (Kumar et al, 2014;Xie et al, 2016) with Rosa26-mT/mG and Sin3a flox/flox mice. All mice were maintained and treatments were carried out according to Institutional Animal Care and Use Committee-approved protocols.…”

Section: Shhmentioning

confidence: 99%

Sin3a regulates epithelial progenitor cell fate during lung development

et al. 2017

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Mechanisms that regulate tissue-specific progenitors for maintenance and differentiation during development are poorly understood. Here, we demonstrate that the co-repressor protein Sin3a is crucial for lung endoderm development. Loss of Sin3a in mouse early foregut endoderm led to a specific and profound defect in lung development with lung buds failing to undergo branching morphogenesis and progressive atrophy of the proximal lung endoderm with complete epithelial loss at later stages of development. Consequently, neonatal pups died at birth due to respiratory insufficiency. Further analysis revealed that loss of Sin3a resulted in embryonic lung epithelial progenitor cells adopting a senescence-like state with permanent cell cycle arrest in G1 phase. This was mediated at least partially through upregulation of the cell cycle inhibitors Cdkn1a and Cdkn2c. At the same time, loss of endodermal Sin3a also disrupted cell differentiation of the mesoderm, suggesting aberrant epithelial-mesenchymal signaling. Together, these findings reveal that Sin3a is an essential regulator for early lung endoderm specification and differentiation.

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Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis

Cited by 118 publications

References 74 publications

Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop

Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop

FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

Sin3a regulates epithelial progenitor cell fate during lung development

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