Identification of the GTPase-activating protein DEP domain containing 1B (DEPDC1B) as a transcriptional target of Pitx2.
Identification of the GTPase-activating protein DEP domain containing 1B (DEPDC1B) as a transcriptional target of Pitx2.
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DOI：
10.1016/j.yexcr.2015.02.008
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发表时间：
2015-04-10
影响因子：
3.7
通讯作者：
Wei Q
中科院分区：
文献类型：
--
作者：
Wu D;Zhu X;Jimenez-Cowell K;Mold AJ;Sollecito CC;Lombana N;Jiao M;Wei Q
Pitx2是一种与bicoid相关的同源盒转录因子，参与调节左右模式和器官发生。然而，只有有限数量的Pitx2下游靶基因已被确定和表征。在这里，我们证明Pitx2是一个转录阻遏物的DEP域包含1B（DEPDC1B）。人类和小鼠DEP结构域的第一个内含子含有1B基因含有多个Pitx2的共有DNA结合位点。染色质免疫沉淀分析显示，Pitx 2，沿着与组蛋白去乙酰化酶1，招募到Depdc 1b的第一个内含子。相反，RNAi介导的Pitx 2缺失不仅增强了Depdc1b第一内含子中组蛋白H4的乙酰化，而且还增加了Depdc1b的蛋白水平。荧光素酶报告基因分析也表明Pitx 2可以抑制人DEPDC1B第一内含子介导的转录活性。DEPDC1B差距域在体外与RAC1的核苷酸结合形式相互作用。此外，DEPDC1B的外源性表达抑制RAC 1的激活，并干扰由鸟嘌呤核苷酸交换因子TRIO诱导的肌动蛋白聚合。此外，DEPDC1B与各种信号分子如U2af2、Erh和Salm相互作用。我们认为Pitx2介导的Depdc1b表达抑制有助于调节多种分子途径，如Rho GT3信号传导。
Pitx2 is a bicoid-related homeobox transcription factor implicated in regulating left-right patterning and organogenesis. However, only a limited number of Pitx2 downstream target genes have been identified and characterized. Here we demonstrate that Pitx2 is a transcriptional repressor of DEP domain containing 1B (DEPDC1B). The first intron of the human and mouse DEP domain containing 1B genes contains multiple consensus DNA-binding sites for Pitx2. Chromatin immunoprecipitation assays revealed that Pitx2, along with histone deacetylase 1, was recruited to the first intron of Depdc1b. In contrast, RNAi-mediated depletion of Pitx2 not only enhanced the acetylation of histone H4 in the first intron of Depdc1b, but also increased the protein level of Depdc1b. Luciferase reporter assays also showed that Pitx2 could repress the transcriptional activity mediated by the first intron of human DEPDC1B. The GAP domain of DEPDC1B interacted with nucleotide-bound forms of RAC1 in vitro. In addition, exogenous expression of DEPDC1B suppressed RAC1 activation and interfered with actin polymerization induced by the guanine nucleotide exchange factor TRIO. Moreover, DEPDC1B interacted with various signaling molecules such as U2af2, Erh, and Salm. We propose that Pitx2-mediated repression of Depdc1b expression contributes to the regulation of multiple molecular pathways, such as Rho GTPase signaling.
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10.1083/jcb.152.3.545
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