GATA4/FOG2 transcriptional complex regulates Lhx9 gene expression in murine heart development

Fatima O Smagulova¹^,3 , Nikolay L Manuylov¹ , Lyndsay L Leach¹ and Sergei G Tevosian¹^,2

¹Department of Genetics, Dartmouth Medical School, Hanover, NH 03755, USA

²Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03755, USA

³Institute of Chemical Biology and Fundamental Medicine, Russian Academy of Sciences, Novosibirsk, Russia

author email corresponding author email

BMC Developmental Biology 2008, 8:67doi:10.1186/1471-213X-8-67


Published:	24 June 2008

Abstract

Background

GATA4 and FOG2 proteins are required for normal cardiac development in mice. It has been proposed that GATA4/FOG2 transcription complex exercises its function through gene activation as well as repression; however, targets of GATA4/FOG2 action in the heart remain elusive.

Results

Here we report identification of the Lhx9 gene as a direct target of the GATA4/FOG2 complex. We demonstrate that the developing mouse heart normally expresses truncated isoforms of Lhx9 – Lhx9α and Lhx9β, and not the Lhx9-HD isoform that encodes a protein with an intact homeodomain. At E9.5 Lhx9α/β expression is prominent in the epicardial primordium, septum transversum while Lhx9-HD is absent from this tissue; in the E11.5 heart LHX9α/β-positive cells are restricted to the epicardial mesothelium. Thereafter in the control hearts Lhx9α/β epicardial expression is promptly down-regulated; in contrast, mouse mutants with Fog2 gene loss fail to repress Lhx9α/β expression. Chromatin immunoprecipitation from the E11.5 hearts demonstrated that Lhx9 is a direct target for GATA4 and FOG2. In transient transfection studies the expression driven by the cis-regulatory regions of Lhx9 was repressed by FOG2 in the presence of intact GATA4, but not the GATA4^kimutant that is impaired in its ability to bind FOG2.

Conclusion

In summary, the Lhx9 gene represents the first direct target of the GATA4/FOG2 repressor complex in cardiac development.