A YAP/TAZ-miR-130/301 molecular circuit exerts systems-level control of fibrosis in a network of human diseases and physiologic conditions

Abstract

The molecular origins of fibrosis affecting multiple tissue beds remain incompletely defined. Previously, we delineated the critical role of the control of extracellular matrix (ECM) stiffening by the mechanosensitive microRNA-130/301 family, as activated by the YAP/TAZ co-transcription factors, in promoting pulmonary hypertension (PH). We hypothesized that similar mechanisms may dictate fibrosis in other tissue beds beyond the pulmonary vasculature. Employing an in silico combination of microRNA target prediction, transcriptomic analysis of 137 human diseases and physiologic states, and advanced gene network modeling, we predicted the microRNA-130/301 family as a master regulator of fibrotic pathways across a cohort of seemingly disparate diseases and conditions. In two such diseases (pulmonary fibrosis and liver fibrosis), inhibition of microRNA-130/301 prevented the induction of ECM modification, YAP/TAZ, and downstream tissue fibrosis. Thus, mechanical forces act through a central feedback circuit between microRNA-130/301 and YAP/TAZ to sustain a common fibrotic phenotype across a network of human physiologic and pathophysiologic states. Such re-conceptualization of interconnections based on shared systems of disease and non-disease gene networks may have broad implications for future convergent diagnostic and therapeutic strategies.

Liver stiffness correlates with serum osteopontin and TAZ expression in human liver cirrhosis

“…Also, a strong correlation was identified between liver tissue stiffness and nuclear TAZ expression. Consistent with our results, it was indicated that during lung, kidney, and chemokine (C‐C motif) ligand 4 (CCL4)–induced liver fibrosis, TAZ is a central player in the mechanical signaling pathway . The association between nuclear TAZ localization and ECM stiffness has been shown in cultured fibroblasts; however, there are sporadic reports on its precise function(s) in the development of liver cirrhosis.…”

Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis

“…While both TAZ and YAP have been implicated in organ fibrosis in other settings, particularly in the lung with links to TGFβ-SMAD signaling or induction of plasminogen activator inhibitor-1 (Liu et al, 2015; Mitani et al, 2009; Piersma et al, 2015; Saito and Nagase, 2015), there are only scattered reports about their roles in liver fibrosis, and none in the setting of NAFLD. For example, a recent study reported an association between microRNA-130/301, which can regulate TAZ and YAP, and CCl 4 -induced liver fibrosis (Bertero et al, 2015), but there were no direct causation or mechanistic data related to the role of TAZ in this process, and we now show that TAZ is not involved in CCl 4 -induced liver fibrosis. Another report showed that knockout of a pair of Hippo factors called Mps One Binder Kinase Activator (MOB)1A/1B in lean, non-NASH mice caused elevated TGFβ-2/3 and liver fibrosis in a manner that was partially dependent on TAZ (Nishio et al, 2016).…”

Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy

“…Here, our findings define the mechanotransduction cascade mediated via YAP/TAZ as a lynchpin between biophysical cues and the metabolic adaptations required for growth in the stiff tumor microenvironment. This reciprocity among YAP/TAZ with upstream (Enzo et al, 2015; Mo et al, 2015; Sorrentino et al, 2014; Wang et al, 2015) and downstream metabolic cues suggests an adjustable, feedback-driven property inherent to this pathway (Bertero et al, 2015a, 2015b; Calvo et al, 2013) and may be partly responsible for individualized “tuning” of the metabolic program within the tumor.…”