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Sci Rep. 2015 Dec 15;5:18277. doi: 10.1038/srep18277.

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

Author information

1
Divisions of Cardiovascular and Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA USA.
2
Regulus Therapeutics, San Diego, CA, USA.
3
National Institutes of Health, Bethesda, MD, USA.
4
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
5
Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA, USA.

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.

PMID:
26667495
PMCID:
PMC4678880
DOI:
10.1038/srep18277
[Indexed for MEDLINE]
Free PMC Article

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