YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis In Vivo
Monroe, Tanner O.; Hill, Matthew C.; Morikawa, Yuka; Leach, John P.; Heallen, Todd; Cao, Shuyi; Krijger, Peter H.L.; de Laat, Wouter; Wehrens, Xander H.T.; Rodney, George G.; Martin, James F.
(2019) Developmental Cell, volume 48, issue 6, pp. 765 - 779.e7
(Article)
Abstract
Specialized adult somatic cells, such as cardiomyocytes (CMs), are highly differentiated with poor renewal capacity, an integral reason underlying organ failure in disease and aging. Among the least renewable cells in the human body, CMs renew approximately 1% annually. Consistent with poor CM turnover, heart failure is the leading cause
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of death. Here, we show that an active version of the Hippo pathway effector YAP, termed YAP5SA, partially reprograms adult mouse CMs to a more fetal and proliferative state. One week after induction, 19% of CMs that enter S-phase do so twice, CM number increases by 40%, and YAP5SA lineage CMs couple to pre-existing CMs. Genomic studies showed that YAP5SA increases chromatin accessibility and expression of fetal genes, partially reprogramming long-lived somatic cells in vivo to a primitive, fetal-like, and proliferative state.
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Keywords: cardiomyocyte proliferation, chromatin accessibility, heart development, heart failure, Hippo pathway, regeneration, reprogramming, transcription, Yap, Molecular Biology, General Biochemistry,Genetics and Molecular Biology, Developmental Biology, Cell Biology
ISSN: 1534-5807
Publisher: Cell Press
Note: Funding Information: This work was supported by Intellectual and Developmental Disability Research Center grant (1U54 HD083092); Eunice Kennedy Shriver NICHD; Baylor College of Medicine Mouse Phenotyping Core NIH (U54 HG006348); NIH (DE 023177, HL 127717, HL 130804, and HL 118761 [J.F.M.]); HL 089898, HL 091947, HL 117641, HL 129570 (X.H.T.W.); AR 061370 (G.G.R.); F31HL136065 (M.C.H.); Vivian L. Smith Foundation, MacDonald Research Fund Award 16RDM001, and LeDucq Foundation Transatlantic Networks of Excellence Cardiovascular Research 14CVD01: “Defining genomic topology of atrial fibrillation” (J.F.M.). Conceptualization, T.O.M. J.P.L. and J.F.M.; Formal Analysis, T.O.M. M.C.H. and P.H.L.K.; Investigation, T.O.M. M.C.H. J.P.L, Y.M. T.H. P.H.L.K. and S.C.; Resources, W.d.L. G.G.R. X.H.T.W. and J.F.M.; Writing – Original Draft, T.O.M.; Writing – Reviewing & Editing, T.O.M. J.P.L, M.C.H. and J.F.M.; Visualization, T.O.M.; Supervision, J.F.M.; Funding Acquisition, M.C.H. W.d.L. G.G.R, X.H.T.W. and J.F.M. J.P.L. and J.F.M. report patent US9732345B2 for Hippo pathway inhibitor. Funding Information: This work was supported by Intellectual and Developmental Disability Research Center grant ( 1U54 HD083092 ); Eunice Kennedy Shriver NICHD ; Baylor College of Medicine Mouse Phenotyping Core NIH ( U54 HG006348 ); NIH ( DE 023177 , HL 127717 , HL 130804 , and HL 118761 [J.F.M.]); HL 089898 , HL 091947 , HL 117641 , HL 129570 (X.H.T.W.); AR 061370 (G.G.R.); F31HL136065 (M.C.H.); Vivian L. Smith Foundation , MacDonald Research Fund Award 16RDM001 , and LeDucq Foundation Transatlantic Networks of Excellence Cardiovascular Research 14CVD01: “Defining genomic topology of atrial fibrillation” (J.F.M.). Publisher Copyright: © 2019 Elsevier Inc.
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