Tomoya Sakamoto1, Timothy R Matsuura1, Shibiao Wan2,3, David M Ryba1, J Unil Kim2,4, Kyoung Jae Won2,4, Ling Lai1, Christopher Petucci1, Nataliya Petrenko1, Kiran Musunuru1, Rick B Vega5, Daniel P Kelly1. 1. From the Cardiovascular Institute (T.S., T.R.M., D.M.R., L.L., C.P., N.P., K.M., D.P.K.). 2. Institute for Diabetes, Obesity and Metabolism, Department of Medicine (S.W., J.K., K.J.W.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia. 3. Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN (S.W.). 4. Biotech Research and Innovation Centre (BRIC) and Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (J.K., K.J.W.). 5. Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL (R.B.V.).
Abstract
RATIONALE: The heart undergoes dramatic developmental changes during the prenatal to postnatal transition, including maturation of cardiac myocyte energy metabolic and contractile machinery. Delineation of the mechanisms involved in cardiac postnatal development could provide new insight into the fetal shifts that occur in the diseased heart and unveil strategies for driving maturation of stem cell-derived cardiac myocytes. OBJECTIVE: To delineate transcriptional drivers of cardiac maturation. METHODS AND RESULTS: We hypothesized that ERR (estrogen-related receptor) α and γ, known transcriptional regulators of postnatal mitochondrial biogenesis and function, serve a role in the broader cardiac maturation program. We devised a strategy to knockdown the expression of ERRα and γ in heart after birth (pn-csERRα/γ [postnatal cardiac-specific ERRα/γ]) in mice. With high levels of knockdown, pn-csERRα/γ knockdown mice exhibited cardiomyopathy with an arrest in mitochondrial maturation. RNA sequence analysis of pn-csERRα/γ knockdown hearts at 5 weeks of age combined with chromatin immunoprecipitation with deep sequencing and functional characterization conducted in human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CM) demonstrated that ERRγ activates transcription of genes involved in virtually all aspects of postnatal developmental maturation, including mitochondrial energy transduction, contractile function, and ion transport. In addition, ERRγ was found to suppress genes involved in fibroblast activation in hearts of pn-csERRα/γ knockdown mice. Disruption of Esrra and Esrrg in mice during fetal development resulted in perinatal lethality associated with structural and genomic evidence of an arrest in cardiac maturation, including persistent expression of early developmental and noncardiac lineage gene markers including cardiac fibroblast signatures. Lastly, targeted deletion of ESRRA and ESRRG in hiPSC-CM derepressed expression of early (transcription factor 21 or TCF21) and mature (periostin, collagen type III) fibroblast gene signatures. CONCLUSIONS: ERRα and γ are critical regulators of cardiac myocyte maturation, serving as transcriptional activators of adult cardiac metabolic and structural genes, an.d suppressors of noncardiac lineages including fibroblast determination.
RATIONALE: The heart undergoes dramatic developmental changes during the prenatal to postnatal transition, including maturation of cardiac myocyte energy metabolic and contractile machinery. Delineation of the mechanisms involved in cardiac postnatal development could provide new insight into the fetal shifts that occur in the diseased heart and unveil strategies for driving maturation of stem cell-derived cardiac myocytes. OBJECTIVE: To delineate transcriptional drivers of cardiac maturation. METHODS AND RESULTS: We hypothesized that ERR (estrogen-related receptor) α and γ, known transcriptional regulators of postnatal mitochondrial biogenesis and function, serve a role in the broader cardiac maturation program. We devised a strategy to knockdown the expression of ERRα and γ in heart after birth (pn-csERRα/γ [postnatal cardiac-specific ERRα/γ]) in mice. With high levels of knockdown, pn-csERRα/γ knockdown mice exhibited cardiomyopathy with an arrest in mitochondrial maturation. RNA sequence analysis of pn-csERRα/γ knockdown hearts at 5 weeks of age combined with chromatin immunoprecipitation with deep sequencing and functional characterization conducted in human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CM) demonstrated that ERRγ activates transcription of genes involved in virtually all aspects of postnatal developmental maturation, including mitochondrial energy transduction, contractile function, and ion transport. In addition, ERRγ was found to suppress genes involved in fibroblast activation in hearts of pn-csERRα/γ knockdown mice. Disruption of Esrra and Esrrg in mice during fetal development resulted in perinatal lethality associated with structural and genomic evidence of an arrest in cardiac maturation, including persistent expression of early developmental and noncardiac lineage gene markers including cardiac fibroblast signatures. Lastly, targeted deletion of ESRRA and ESRRG in hiPSC-CM derepressed expression of early (transcription factor 21 or TCF21) and mature (periostin, collagen type III) fibroblast gene signatures. CONCLUSIONS:ERRα and γ are critical regulators of cardiac myocyte maturation, serving as transcriptional activators of adult cardiac metabolic and structural genes, an.d suppressors of noncardiac lineages including fibroblast determination.
Authors: Janice M Huss; Ken-ichi Imahashi; Catherine R Dufour; Carla J Weinheimer; Michael Courtois; Atilla Kovacs; Vincent Giguère; Elizabeth Murphy; Daniel P Kelly Journal: Cell Metab Date: 2007-07 Impact factor: 27.287
Authors: Zhiqiang Lin; Alexander von Gise; Pingzhu Zhou; Fei Gu; Qing Ma; Jianming Jiang; Allan L Yau; Jessica N Buck; Katryna A Gouin; Pim R R van Gorp; Bin Zhou; Jinghai Chen; Jonathan G Seidman; Da-Zhi Wang; William T Pu Journal: Circ Res Date: 2014-05-15 Impact factor: 17.367
Authors: Bence Daniel; Gergely Nagy; Nasun Hah; Attila Horvath; Zsolt Czimmerer; Szilard Poliska; Tibor Gyuris; Jiri Keirsse; Conny Gysemans; Jo A Van Ginderachter; Balint L Balint; Ronald M Evans; Endre Barta; Laszlo Nagy Journal: Genes Dev Date: 2014-07-15 Impact factor: 11.361
Authors: Erin L Brown; Bethany C Hazen; Elodie Eury; Jean-Sébastien Wattez; Marin L Gantner; Verena Albert; Sarah Chau; Manuel Sanchez-Alavez; Bruno Conti; Anastasia Kralli Journal: iScience Date: 2018-04-27
Authors: Helen E Collins; Mariame Selma Kane; Silvio H Litovsky; Victor M Darley-Usmar; Martin E Young; John C Chatham; Jianhua Zhang Journal: Front Aging Date: 2021-05-06
Authors: Heather L Ciallella; Daniel P Russo; Swati Sharma; Yafan Li; Eddie Sloter; Len Sweet; Heng Huang; Hao Zhu Journal: Environ Sci Technol Date: 2022-04-22 Impact factor: 11.357
Authors: Shunsuke Funakoshi; Ian Fernandes; Olya Mastikhina; Dan Wilkinson; Thinh Tran; Wahiba Dhahri; Amine Mazine; Donghe Yang; Benjamin Burnett; Jeehoon Lee; Stephanie Protze; Gary D Bader; Sara S Nunes; Michael Laflamme; Gordon Keller Journal: Nat Commun Date: 2021-05-26 Impact factor: 14.919
Authors: Michela Grillo; Carolyn Palmer; Nadine Holmes; Fei Sang; Andrew C Larner; Rahul Bhosale; Peter E Shaw Journal: PLoS One Date: 2020-12-17 Impact factor: 3.240