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

Female Heart / physiopathology Humans Male Receptors, Progesterone / metabolism Sex Factors
chromatin hormone human development progesterone sexual maturation transcription factor

Journal

Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763

Informations de publication

Date de publication:
20 04 2021
Historique:
pubmed: 9 3 2021
medline: 29 12 2021
entrez: 8 3 2021
Statut: ppublish

Résumé

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. 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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1161/CIRCULATIONAHA.120.051921 PMID: 33682422 PMC: PMC8055196
pubmed: 33682422
doi: 10.1161/CIRCULATIONAHA.120.051921
pmc: PMC8055196
doi:

Substances chimiques

Receptors, Progesterone 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1614-1628

Commentaires et corrections

Type : CommentIn

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Auteurs

Choon Boon 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.

Belinda 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.

Mark 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.).

Haloom 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.).

Richard J Mills (RJ)

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

Kevin I 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.).

Kwaku D 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.

Ravi K R 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.

Holly K 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.

Doan T Dinh (DT)

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

Menno 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.

Celine J 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.

Antony 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.).

Harikrishnan 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.).

Alejandro 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.

Leanne M D 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.

Rebecca L Robker (RL)

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

Paul 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.).

Cristobal G 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.).

Sean Lal (S)

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

Adam T 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.

Igor E 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.

David A 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.

Assam 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.

Alicia 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.).

James E 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.).

Enzo R 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.).

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Classifications MeSH

questionsmedicales.fr › Système cardiovasculaire › Coeur › Sex-Specific Control of Human Heart Maturation...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Sex-Specific Control of Human Heart Maturation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteurs à la progestérone › Sex-Specific Control of Human Heart Maturation...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Facteurs épidémiologiques › Facteurs sexuels › Sex-Specific Control of Human Heart Maturation...