GATA6 is a regulator of sinus node development and heart rhythm

Proc Natl Acad Sci U S A. 2021 Jan 5;118(1):e2007322118. doi: 10.1073/pnas.2007322118. Epub 2020 Dec 21.

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.

Keywords: GATA proteins; TBX3; cardiac conduction system; heart development; sinus node.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / physiopathology
  • Cell Differentiation / genetics
  • GATA6 Transcription Factor / genetics
  • GATA6 Transcription Factor / metabolism*
  • Gene Expression Regulation, Developmental / genetics
  • Heart Rate / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organogenesis
  • Sinoatrial Node / embryology*
  • Sinoatrial Node / physiology
  • T-Box Domain Proteins / genetics

Substances

  • GATA6 Transcription Factor
  • Gata6 protein, mouse
  • T-Box Domain Proteins

Grant support