Single-Cell Resolution of Temporal Gene Expression During Heart Development

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2016 Nov 15

PMID 27840107

Citations 245

Authors

Daniel M DeLaughter

Alexander G Bick

Hiroko Wakimoto

David McKean

Joshua M Gorham

Irfan S Kathiriya

John T Hinson

Jason Homsy

Jesse Gray

William Pu

Benoit G Bruneau

J G Seidman

Christine E Seidman

Affiliations

Soon will be listed here.

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.

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References

Tanaka M, Chen Z, Bartunkova S, Yamasaki N, Izumo S . The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development. 1999; 126(6):1269-80. DOI: 10.1242/dev.126.6.1269. View

Liberatore C, Yutzey K . Ventricular expression of tbx5 inhibits normal heart chamber development. Dev Biol. 2000; 223(1):169-80. DOI: 10.1006/dbio.2000.9748. View

Biben C, Weber R, Kesteven S, Stanley E, McDonald L, Elliott D . Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circ Res. 2000; 87(10):888-95. DOI: 10.1161/01.res.87.10.888. View

Braybrook C, Warry G, Howell G, Arnason A, Bjornsson A, Moore G . Identification and characterization of KLHL4, a novel human homologue of the Drosophila Kelch gene that maps within the X-linked cleft palate and Ankyloglossia (CPX) critical region. Genomics. 2001; 72(2):128-36. DOI: 10.1006/geno.2000.6478. View

Bruneau B, Nemer G, Schmitt J, Charron F, Robitaille L, Caron S . A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell. 2001; 106(6):709-21. DOI: 10.1016/s0092-8674(01)00493-7. View

Pujades C, Dunon D . Melanoma Cell Adhesion Molecule (MCAM) expression in the myogenic lineage during early chick embryonic development. Int J Dev Biol. 2002; 46(2):263-6. DOI: 10.1387/ijdb.011493. View

Elliott D, Kirk E, Yeoh T, Chandar S, McKenzie F, Taylor P . Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome. J Am Coll Cardiol. 2003; 41(11):2072-6. DOI: 10.1016/s0735-1097(03)00420-0. View

Koshiba-Takeuchi K, Takeuchi J, Arruda E, Kathiriya I, Mo R, Hui C . Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Nat Genet. 2005; 38(2):175-83. DOI: 10.1038/ng1707. View

Ambrosino C, Iwata T, Scafoglio C, Mallardo M, Klein R, Nebreda A . TEF-1 and C/EBPbeta are major p38alpha MAPK-regulated transcription factors in proliferating cardiomyocytes. Biochem J. 2006; 396(1):163-72. PMC: 1449985. DOI: 10.1042/BJ20051502. View

10.

Luo M, Li Y, Yang K . Fibrosis of collagen I and remodeling of connexin 43 in atrial myocardium of patients with atrial fibrillation. Cardiology. 2006; 107(4):248-53. DOI: 10.1159/000095501. View

11.

Huang D, Sherman B, Tan Q, Kir J, Liu D, Bryant D . DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 2007; 35(Web Server issue):W169-75. PMC: 1933169. DOI: 10.1093/nar/gkm415. View

12.

Wagner M, Siddiqui M . Signal transduction in early heart development (I): cardiogenic induction and heart tube formation. Exp Biol Med (Maywood). 2007; 232(7):852-65. View

13.

Koo J, Smiley M, Lovering R, Margolis F . Bex1 knock out mice show altered skeletal muscle regeneration. Biochem Biophys Res Commun. 2007; 363(2):405-10. PMC: 2265538. DOI: 10.1016/j.bbrc.2007.08.186. View

14.

Cheroki C, Krepischi-Santos A, Szuhai K, Brenner V, Kim C, Otto P . Genomic imbalances associated with mullerian aplasia. J Med Genet. 2007; 45(4):228-32. DOI: 10.1136/jmg.2007.051839. View

15.

Monzen K, Ito Y, Naito A, Kasai H, Hiroi Y, Hayashi D . A crucial role of a high mobility group protein HMGA2 in cardiogenesis. Nat Cell Biol. 2008; 10(5):567-74. DOI: 10.1038/ncb1719. View

16.

Ieda M, Tsuchihashi T, Ivey K, Ross R, Hong T, Shaw R . Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev Cell. 2009; 16(2):233-44. PMC: 2664087. DOI: 10.1016/j.devcel.2008.12.007. View

17.

Trapnell C, Pachter L, Salzberg S . TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009; 25(9):1105-11. PMC: 2672628. DOI: 10.1093/bioinformatics/btp120. View

18.

Tian Y, Yuan L, Goss A, Wang T, Yang J, Lepore J . Characterization and in vivo pharmacological rescue of a Wnt2-Gata6 pathway required for cardiac inflow tract development. Dev Cell. 2010; 18(2):275-87. PMC: 2846539. DOI: 10.1016/j.devcel.2010.01.008. View

19.

Medic S, Ziman M . PAX3 expression in normal skin melanocytes and melanocytic lesions (naevi and melanomas). PLoS One. 2010; 5(4):e9977. PMC: 2858648. DOI: 10.1371/journal.pone.0009977. View

20.

Dahle O, Kumar A, Kuehn M . Nodal signaling recruits the histone demethylase Jmjd3 to counteract polycomb-mediated repression at target genes. Sci Signal. 2010; 3(127):ra48. PMC: 6953396. DOI: 10.1126/scisignal.2000841. View