title: 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.
authors.affiliation: Divisions of Cardiovascular and Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertero
authors.affiliation: Divisions of Cardiovascular and Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Cottrill
authors.affiliation: Divisions of Cardiovascular and Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Annis
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: Balkrishen
authors.initials: B
authors.lastname: Bhat
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: Bernadette R
authors.initials: BR
authors.lastname: Gochuico
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Osorio
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rosas
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Haley
authors.affiliation: Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Corey
authors.affiliation: Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Nelson Chau
authors.affiliation: Divisions of Cardiovascular and Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA USA.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Chan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D004195:Disease Models, Animal; D005109:Extracellular Matrix; D005355:Fibrosis; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001057:Apolipoproteins E; D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D047908:Intracellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; C554019:MIRN130 microRNA, human; C550735:MIRN301A microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C098773:low density lipoprotein receptor-related protein 8