title: Single-Cell Resolution of Temporal Gene Expression during Heart Development.
abstract: Activation of complex molecular programs in specific cell lineages governs mammalian heart development, from a primordial linear tube to a four-chamber organ. To characterize lineage-specific, spatiotemporal developmental programs, we performed single-cell RNA sequencing of >1,200 murine cells isolated at seven time points spanning embryonic day 9.5 (primordial heart tube) to postnatal day 21 (mature heart). Using unbiased transcriptional data, we classified cardiomyocytes, endothelial cells, and fibroblast-enriched cells, thus identifying markers for temporal and chamber-specific developmental programs. By harnessing these datasets, we defined developmental ages of human and mouse pluripotent stem-cell-derived cardiomyocytes and characterized lineage-specific maturation defects in hearts of mice with heterozygous mutations in Nkx2.5 that cause human heart malformations. This spatiotemporal transcriptome analysis of heart development reveals lineage-specific gene programs underlying normal cardiac development and congenital heart disease.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: DeLaughter
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bick
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David
authors.initials: D
authors.lastname: McKean
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Gorham
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 92868, USA.
authors.forename: Irfan S
authors.initials: IS
authors.lastname: Kathiriya
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Hinson
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Homsy
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Gray
authors.affiliation: Department of Cardiology, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: William
authors.initials: W
authors.lastname: Pu
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Department of Pediatrics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Division, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: cseidman@genetics.med.harvard.edu.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D057895:Haploinsufficiency / Q000235:genetics; D006321:Heart / Q000196:embryology*; D006325:Heart Atria / Q000166:cytology; D006352:Heart Ventricles / Q000166:cytology; D000072576:Homeobox Protein Nkx-2.5 / Q000378:metabolism; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis / Q000379:methods*; D013997:Time Factors; D059467:Transcriptome / Q000235:genetics
chemical_list: D000072576:Homeobox Protein Nkx-2.5; C484469:Nkx2-5 protein, mouse
keywords: ECM; Nkx2.5; RNA-seq; atria; cardiogenesis; cardiomyocyte maturation; heart; single cell; ventricle