Sex-Specific Control of Human Heart Maturation by the Progesterone Receptor-Reference-Cited by-同舟云学术

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

Published:2021-04-20 Issue:16 Volume:143 Page:1614-1628
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Sim Choon Boon¹²,Phipson Belinda¹³^ORCID,Ziemann Mark⁴⁵⁶,Rafehi Haloom⁴⁶,Mills Richard J.⁷,Watt Kevin I.³⁸⁶^ORCID,Abu-Bonsrah Kwaku D.¹²⁹,Kalathur Ravi K.R.¹²,Voges Holly K.¹⁹^ORCID,Dinh Doan T.¹⁰,ter Huurne Menno¹²^ORCID,Vivien Celine J.¹²,Kaspi Antony⁴⁶,Kaipananickal Harikrishnan⁴⁶,Hidalgo Alejandro¹⁹^ORCID,Delbridge Leanne M.D.²¹¹,Robker Rebecca L.¹⁰,Gregorevic Paul¹¹⁸⁶,dos Remedios Cristobal G.¹²¹³^ORCID,Lal Sean¹²^ORCID,Piers Adam T.¹²,Konstantinov Igor E.¹²¹⁴⁹,Elliott David A.¹²⁹,El-Osta Assam¹^ORCID,Oshlack Alicia⁴⁶¹⁵,Hudson James E.⁷¹⁶,Porrello Enzo R.¹²¹¹⁸¹⁶^ORCID

Affiliation:

1. 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.

2. 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.

3. Peter MacCallum Cancer Centre (B.P., A.O.), University of Melbourne, Victoria, Australia.

4. Department of Diabetes, Central Clinical School, Alfred Centre, Monash University, Melbourne, Victoria, Australia (M.Z., H.R., A.K., H.K., A.E.-O.).

5. School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, Australia (M.Z.).

6. Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.Z., H.R., K.I.W., A.K., H.K., P.G., A.E.-O.).

7. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (R.J.M., J.E.H.).

8. Centre for Muscle Research (K.I.W., P.G., E.R.P.), University of Melbourne, Victoria, Australia.

9. 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.

10. Robinson Research Institute, The University of Adelaide, South Australia, Australia (D.T.D., R.L.R.).

11. Department of Anatomy and Physiology (K.I.W., L.M.D.D., P.G., E.R.P.), University of Melbourne, Victoria, Australia.

12. School of Medical Sciences, The University of Sydney, New South Wales, Australia (C.G.d.R., S.L.).

13. Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia (C.G.d.R.).

14. Department of Cardiac Surgery (I.E.K.), The Royal Children’s Hospital, Melbourne, Victoria, Australia.

15. 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.).

16. Centre for Cardiac and Vascular Biology, School of Biomedical Sciences, The University of Queensland, Brisbane, Australia (J.E.H., E.R.P.).

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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