GATA4/FOG2 transcriptional complex regulates Lhx9 gene expression in murine heart development.
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 - Lhx9alpha and Lhx9beta, and not the Lhx9-HD isoform that encodes a protein with an intact homeodomain. At E9.5 Lhx9alpha/beta expression is prominent in the epicardial primordium, septum transversum while Lhx9-HD is absent from this tissue; in the E11.5 heart LHX9alpha/beta-positive cells are restricted to the epicardial mesothelium. Thereafter in the control hearts Lhx9alpha/beta epicardial expression is promptly down-regulated; in contrast, mouse mutants with Fog2 gene loss fail to repress Lhx9alpha/beta 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 GATA4ki mutant that is impaired in its ability to bind FOG2.


CONCLUSIONS
In summary, the Lhx9 gene represents the first direct target of the GATA4/FOG2 repressor complex in cardiac development.
Smagulova
Fatima O
FO
Department of Genetics, Dartmouth Medical School, Hanover, NH 03755, USA. fatimas_369@hotmail.com
Manuylov
Nikolay L
NL
Leach
Lyndsay L
LL
Tevosian
Sergei G
SG
D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D050991:GATA4 Transcription Factor / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006321:Heart / Q000254:growth & development*; D018398:Homeodomain Proteins / Q000235:genetics*; D060850:LIM-Homeodomain Proteins; D051379:Mice; D046912:Multiprotein Complexes; D020033:Protein Isoforms; D014018:Tissue Distribution; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C117058:Lhx9 protein, mouse; D046912:Multiprotein Complexes; D020033:Protein Isoforms; D014157:Transcription Factors; C492170:Zfpm2 protein, mouse