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GATA4/FOG2转录复合物在小鼠心脏发育过程中调节Lhx9基因的表达。

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

作者信息

Smagulova Fatima O, Manuylov Nikolay L, Leach Lyndsay L, Tevosian Sergei G

机构信息

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

出版信息

BMC Dev Biol. 2008 Jun 24;8:67. doi: 10.1186/1471-213X-8-67.

DOI:10.1186/1471-213X-8-67
PMID:18577233
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2447832/
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 - 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.

CONCLUSION

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

摘要

背景

GATA4和FOG2蛋白是小鼠正常心脏发育所必需的。有人提出，GATA4/FOG2转录复合物通过基因激活和抑制来发挥其功能；然而，GATA4/FOG2在心脏中的作用靶点仍然不清楚。

结果

在此我们报告鉴定出Lhx9基因是GATA4/FOG2复合物的直接靶点。我们证明，发育中的小鼠心脏正常表达Lhx9的截短异构体——Lhx9α和Lhx9β，而不表达编码具有完整同源结构域蛋白的Lhx9-HD异构体。在胚胎第9.5天，Lhx9α/β在原始心外膜、横隔中表达显著，而该组织中不存在Lhx9-HD；在胚胎第11.5天的心脏中，LHX9α/β阳性细胞局限于心外膜间皮。此后，在对照心脏中，Lhx9α/β的心外膜表达迅速下调；相反，Fog2基因缺失的小鼠突变体无法抑制Lhx9α/β的表达。对胚胎第11.5天心脏进行的染色质免疫沉淀表明Lhx9是GATA4和FOG2的直接靶点。在瞬时转染研究中，在完整的GATA4存在的情况下，Lhx9顺式调控区驱动的表达被FOG2抑制，但不能被结合FOG2能力受损的GATA4ki突变体抑制。

结论

总之，Lhx9基因是心脏发育中GATA4/FOG2抑制复合物的首个直接靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0433/2447832/cf95cc10290b/1471-213X-8-67-8.jpg
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