GATA6 is a regulator of sinus node development and heart rhythm

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Significance

GATA6 is a key regulator of sinus node (SAN) development. Loss of one Gata6 allele disrupts patterning and size of the SAN. GATA6 plays cell autonomous as well as non-cell autonomous functions in several cell types required for proper SAN development and function. Haploinsufficiency of Gata6 in mice leads to electrophysiological alterations and increases susceptibility to develop arrhythmias. GATA6 is critical for pacemaker cell differentiation and cardiac conduction.

Abstract

The sinus node (SAN) is the primary pacemaker of the human heart, and abnormalities in its structure or function cause sick sinus syndrome, the most common reason for electronic pacemaker implantation. Here we report that transcription factor GATA6, whose mutations in humans are linked to arrhythmia, is highly expressed in the SAN and its haploinsufficiency in mice results in hypoplastic SANs and rhythm abnormalities. Cell-specific deletion reveals a requirement for GATA6 in various SAN lineages. Mechanistically, GATA6 directly activates key regulators of the SAN genetic program in conduction and nonconduction cells, such as TBX3 and EDN1, respectively. The data identify GATA6 as an important regulator of the SAN and provide a molecular basis for understanding the conduction abnormalities associated with GATA6 mutations in humans. They also suggest that GATA6 may be a potential modifier of the cardiac pacemaker.

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Most cited references 44

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GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5.

Vidu Garg, Irfan S Kathiriya, Robert Barnes … (2003)

Congenital heart defects (CHDs) are the most common developmental anomaly and are the leading non-infectious cause of mortality in newborns. Only one causative gene, NKX2-5, has been identified through genetic linkage analysis of pedigrees with non-syndromic CHDs. Here, we show that isolated cardiac septal defects in a large pedigree were linked to chromosome 8p22-23. A heterozygous G296S missense mutation of GATA4, a transcription factor essential for heart formation, was found in all available affected family members but not in any control individuals. This mutation resulted in diminished DNA-binding affinity and transcriptional activity of Gata4. Furthermore, the Gata4 mutation abrogated a physical interaction between Gata4 and TBX5, a T-box protein responsible for a subset of syndromic cardiac septal defects. Conversely, interaction of Gata4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. In a second family, we identified a frame-shift mutation of GATA4 (E359del) that was transcriptionally inactive and segregated with cardiac septal defects. These results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5.

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A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease.

B. Bruneau, G Nemer, J. Schmitt … (2001)

Heterozygous Tbx5(del/+) mice were generated to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities seen in Holt-Oram syndrome. Tbx5 deficiency in homozygous mice (Tbx5(del/del)) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart. Surprisingly, Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription, implicating these as Tbx5 target genes and providing a mechanism by which 50% reduction of T-box transcription factors cause disease. Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated. These studies provide one potential explanation for Holt-Oram syndrome conduction system defects, suggest mechanisms for intrafamilial phenotypic variability, and account for related cardiac malformations caused by other transcription factor mutations.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 07 January 2021

Publication date (Electronic): 28 December 2020

Publication date PMC-release: 28 December 2020

Volume: 118

Issue: 1

Electronic Location Identifier: e2007322118

Affiliations

[1] ^aMolecular Genetics and Cardiac Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa , Ottawa, ON, Canada K1H 8M5;

[2] ^bCardiovascular Research Center, Harvard Medical School, Boston, MA 02115;

[3] ^cCardiovascular Electrophysiology Laboratory, University of Ottawa Heart Institute, University of Ottawa , Ottawa, ON, Canada K1Y 4W7;

[4] ^dResearch Center, Montreal Heart Institute , Montreal, QC, Canada H1T 1C8;

[5] ^eFaculty of Pharmacy, Université de Montréal , Montréal, QC, Canada H3T 1J4

Author notes

²To whom correspondence may be addressed. Email: mona.nemer@ 123456uottawa.ca .

Edited by Christine E. Seidman, Howard Hughes Medical Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, and approved October 19, 2020 (received for review April 16, 2020)

Author contributions: L.G. and M.N. designed research; L.G., A.Y., J.W., A.L., and M.J. performed research; W.L. and C.F. contributed new reagents/analytic tools; L.G., A.Y., J.W., A.L., M.J., H.K., W.L., C.F., and M.N. analyzed data and interpreted results; L.G. and M.N. wrote the paper.

¹A.Y. and J.W. contributed equally to this work.