Sex-Specific Control of Human Heart Maturation by the Progesterone Receptor.

Autor:	Sim CB; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (C.B.S., K.D.A.-B., R.K.R.K., M.t.H., C.J.V., L.M.D.D., A.T.P., I.E.K., D.A.E., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia., Phipson B; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Peter MacCallum Cancer Centre (B.P., A.O.), University of Melbourne, Victoria, Australia., Ziemann M; Department of Diabetes, Central Clinical School, Alfred Centre, Monash University, Melbourne, Victoria, Australia (M.Z., H.R., A.K., H.K., A.E.-O.).; School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, Australia (M.Z.).; Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.Z., H.R., K.I.W., A.K., H.K., P.G., A.E.-O.)., Rafehi H; Department of Diabetes, Central Clinical School, Alfred Centre, Monash University, Melbourne, Victoria, Australia (M.Z., H.R., A.K., H.K., A.E.-O.).; Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.Z., H.R., K.I.W., A.K., H.K., P.G., A.E.-O.)., Mills RJ; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (R.J.M., J.E.H.)., Watt KI; Peter MacCallum Cancer Centre (B.P., A.O.), University of Melbourne, Victoria, Australia.; Centre for Muscle Research (K.I.W., P.G., E.R.P.), University of Melbourne, Victoria, Australia.; Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.Z., H.R., K.I.W., A.K., H.K., P.G., A.E.-O.)., Abu-Bonsrah KD; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (C.B.S., K.D.A.-B., R.K.R.K., M.t.H., C.J.V., L.M.D.D., A.T.P., I.E.K., D.A.E., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; School of Biomedical Sciences, and Department of Paediatrics (K.D.A.-B., H.K.V., A.H., I.E.K., D.A.E.), University of Melbourne, Victoria, Australia., Kalathur RKR; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (C.B.S., K.D.A.-B., R.K.R.K., M.t.H., C.J.V., L.M.D.D., A.T.P., I.E.K., D.A.E., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia., Voges HK; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; School of Biomedical Sciences, and Department of Paediatrics (K.D.A.-B., H.K.V., A.H., I.E.K., D.A.E.), University of Melbourne, Victoria, Australia., Dinh DT; Robinson Research Institute, The University of Adelaide, South Australia, Australia (D.T.D., R.L.R.)., Ter Huurne M; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (C.B.S., K.D.A.-B., R.K.R.K., M.t.H., C.J.V., L.M.D.D., A.T.P., I.E.K., D.A.E., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia., Vivien CJ; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (C.B.S., K.D.A.-B., R.K.R.K., M.t.H., C.J.V., L.M.D.D., A.T.P., I.E.K., D.A.E., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia., Kaspi A; Department of Diabetes, Central Clinical School, Alfred Centre, Monash University, Melbourne, Victoria, Australia (M.Z., H.R., A.K., H.K., A.E.-O.).; Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.Z., H.R., K.I.W., A.K., H.K., P.G., A.E.-O.)., Kaipananickal H; Department of Diabetes, Central Clinical School, Alfred Centre, Monash University, Melbourne, Victoria, Australia (M.Z., H.R., A.K., H.K., A.E.-O.).; Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.Z., H.R., K.I.W., A.K., H.K., P.G., A.E.-O.)., Hidalgo A; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; School of Biomedical Sciences, and Department of Paediatrics (K.D.A.-B., H.K.V., A.H., I.E.K., D.A.E.), University of Melbourne, Victoria, Australia., Delbridge LMD; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (C.B.S., K.D.A.-B., R.K.R.K., M.t.H., C.J.V., L.M.D.D., A.T.P., I.E.K., D.A.E., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Department of Anatomy and Physiology (K.I.W., L.M.D.D., P.G., E.R.P.), University of Melbourne, Victoria, Australia., Robker RL; Robinson Research Institute, The University of Adelaide, South Australia, Australia (D.T.D., R.L.R.)., Gregorevic P; Department of Anatomy and Physiology (K.I.W., L.M.D.D., P.G., E.R.P.), University of Melbourne, Victoria, Australia.; Centre for Muscle Research (K.I.W., P.G., E.R.P.), University of Melbourne, Victoria, Australia.; Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.Z., H.R., K.I.W., A.K., H.K., P.G., A.E.-O.)., Dos Remedios CG; School of Medical Sciences, The University of Sydney, New South Wales, Australia (C.G.d.R., S.L.).; Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia (C.G.d.R.)., Lal S; School of Medical Sciences, The University of Sydney, New South Wales, Australia (C.G.d.R., S.L.)., Piers AT; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (C.B.S., K.D.A.-B., R.K.R.K., M.t.H., C.J.V., L.M.D.D., A.T.P., I.E.K., D.A.E., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia., Konstantinov IE; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (C.B.S., K.D.A.-B., R.K.R.K., M.t.H., C.J.V., L.M.D.D., A.T.P., I.E.K., D.A.E., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Department of Cardiac Surgery (I.E.K.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; School of Biomedical Sciences, and Department of Paediatrics (K.D.A.-B., H.K.V., A.H., I.E.K., D.A.E.), University of Melbourne, Victoria, Australia., Elliott DA; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (C.B.S., K.D.A.-B., R.K.R.K., M.t.H., C.J.V., L.M.D.D., A.T.P., I.E.K., D.A.E., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; School of Biomedical Sciences, and Department of Paediatrics (K.D.A.-B., H.K.V., A.H., I.E.K., D.A.E.), University of Melbourne, Victoria, Australia., El-Osta A; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia., Oshlack A; Department of Diabetes, Central Clinical School, Alfred Centre, Monash University, Melbourne, Victoria, Australia (M.Z., H.R., A.K., H.K., A.E.-O.).; Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.Z., H.R., K.I.W., A.K., H.K., P.G., A.E.-O.).; Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, Li Ka Shing Institute of Health Sciences, and The Chinese University of Hong Kong, China (A.E.-O.)., Hudson JE; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (R.J.M., J.E.H.).; Centre for Cardiac and Vascular Biology, School of Biomedical Sciences, The University of Queensland, Brisbane, Australia (J.E.H., E.R.P.)., Porrello ER; Murdoch Children's Research Institute (C.B.S., B.P., K.D.A.-B., R.K.R.K., H.K.V., M.t.H., C.J.V., A.H., A.T.P., I.E.K., D.A.E., A.O., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine (C.B.S., K.D.A.-B., R.K.R.K., M.t.H., C.J.V., L.M.D.D., A.T.P., I.E.K., D.A.E., E.R.P.), The Royal Children's Hospital, Melbourne, Victoria, Australia.; Department of Anatomy and Physiology (K.I.W., L.M.D.D., P.G., E.R.P.), University of Melbourne, Victoria, Australia.; Centre for Muscle Research (K.I.W., P.G., E.R.P.), University of Melbourne, Victoria, Australia.; Centre for Cardiac and Vascular Biology, School of Biomedical Sciences, The University of Queensland, Brisbane, Australia (J.E.H., E.R.P.).
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2021 Apr 20; Vol. 143 (16), pp. 1614-1628. Date of Electronic Publication: 2021 Mar 08.
DOI:	10.1161/CIRCULATIONAHA.120.051921
Abstrakt:	Background: Despite in-depth knowledge of the molecular mechanisms controlling embryonic heart development, little is known about the signals governing postnatal maturation of the human heart. Methods: Single-nucleus RNA sequencing of 54 140 nuclei from 9 human donors was used to profile transcriptional changes in diverse cardiac cell types during maturation from fetal stages to adulthood. Bulk RNA sequencing and the Assay for Transposase-Accessible Chromatin using sequencing were used to further validate transcriptional changes and to profile alterations in the chromatin accessibility landscape in purified cardiomyocyte nuclei from 21 human donors. Functional validation studies of sex steroids implicated in cardiac maturation were performed in human pluripotent stem cell-derived cardiac organoids and mice. Results: Our data identify the progesterone receptor as a key mediator of sex-dependent transcriptional programs during cardiomyocyte maturation. Functional validation studies in human cardiac organoids and mice demonstrate that the progesterone receptor drives sex-specific metabolic programs and maturation of cardiac contractile properties. Conclusions: These data provide a blueprint for understanding human heart maturation in both sexes and reveal an important role for the progesterone receptor in human heart development.
Databáze:	MEDLINE
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