GATA4/FOG2 transcriptional complex regulates Lhx9 gene expression in murine heart development.
GATA4/FOG2 transcriptional complex regulates Lhx9 gene expression in murine heart development.
复制标题
GATA4/FOG2转录复合物调节鼠心脏发育中的LHX9基因表达。
DOI：
10.1186/1471-213x-8-67
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发表时间：
2008-06-24
影响因子：
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通讯作者：
Tevosian, Sergei G.
中科院分区：
文献类型：
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作者：
Smagulova, Fatima O.;Manuylov, Nikolay L.;Leach, Lyndsay L.;Tevosian, Sergei G.
GATA 4和FOG 2蛋白是小鼠正常心脏发育所必需的。已经提出GATA 4/FOG 2转录复合物通过基因激活以及抑制来行使其功能;然而，心脏中GATA 4/FOG 2作用的靶点仍然难以捉摸。在这里，我们报告鉴定Lhx 9基因作为GATA 4/FOG 2复合物的直接靶标。我们证明发育中的小鼠心脏正常表达Lhx 9-Lhx 9 α和Lhx 9 β的截短亚型，而不是编码具有完整同源结构域的蛋白质的Lhx 9-HD亚型。在E9.5，Lhx 9 α/β表达在心外膜原基、横隔中显著，而Lhx 9-HD在该组织中不存在;在E11.5心脏中，Lhx 9 α/β阳性细胞限于心外膜间皮。此后，在对照心脏中，Lhx 9 α/β心外膜表达迅速下调;相反，Fog 2基因缺失的小鼠突变体不能抑制Lhx 9 α/β表达。来自E11.5心脏的染色质免疫沉淀证明Lhx 9是GATA 4和FOG 2的直接靶标。在瞬时转染研究中，由Lhx 9的顺式调节区驱动的表达在完整GATA 4存在下被FOG 2抑制，但不抑制GATA 4ki突变体结合FOG 2的能力受损。总之，Lhx 9基因代表了心脏发育中GATA 4/FOG 2阻遏复合物的第一个直接靶点。
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. 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 GATA4ki mutant that is impaired in its ability to bind FOG2. In summary, the Lhx9 gene represents the first direct target of the GATA4/FOG2 repressor complex in cardiac development.