A potential molecular pathogenesis of cardiac/laterality defects in Oculo-Facio-Cardio-Dental syndrome.
A potential molecular pathogenesis of cardiac/laterality defects in Oculo-Facio-Cardio-Dental syndrome.
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DOI：
10.1016/j.ydbio.2014.01.003
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发表时间：
2014-03-01
影响因子：
2.7
通讯作者：
Kato, Yoichi
中科院分区：
文献类型：
--
作者：
Tanaka, Koichi;Kato, Akiko;Angelocci, Chelsea;Watanabe, Minoru;Kato, Yoichi
Pitx 2是迄今为止已知的左右（LR）级联的最后一个效应子，在LR不对称的模式中起着至关重要的作用。在非洲爪蟾胚胎中，Pitx 2基因在左侧板中胚层（LPM）的表达直接受Xnr 1信号转导的调控，而Xnr 1信号转导则由Smads和FoxH 1介导。以往的研究表明，Pitx 2基因在左LPM中的抑制是眼-面-牙-牙（OFCD）综合征中心脏/偏侧缺陷的潜在原因，已知该综合征是由BCL 6辅抑制因子（BCOR）基因突变引起的。最近，我们的工作揭示了BCL 6/BCOR复合物阻断Notch依赖的转录活性，以保护左侧LPM中Pitx 2的表达免受Notch信号传导的抑制活性。这些研究表明，BCOR功能障碍引起的左侧LPM不受控制的Notch活性可能导致OFCD综合征的心脏/偏侧性缺陷。然而，这种Notch依赖的Pitx 2基因转录抑制机制仍然未知。转录抑制因子ESR 1作用于Notch信号下游，通过与Pitx 2基因的左侧特异性增强子（ASE）区域结合并募集组蛋白去乙酰化酶1（HDAC 1）到该区域来抑制Pitx 2基因的表达。一旦HDAC 1被拴系，组蛋白乙酰转移酶p300就不再被招募到ASE区域上的Xnr 1依赖性转录复合物中，导致左侧LPM中Pitx 2基因的抑制。本研究揭示了Pitx 2基因转录的调控机制，为进一步了解OFCD综合征的发病机制提供了理论依据。
Pitx2 is the last effector of the left-right (LR) cascade known to date and plays a crucial role in the patterning of LR asymmetry. In Xenopus embryos, the expression of Pitx2 gene in the left lateral plate mesoderm (LPM) is directly regulated by Xnr1 signaling, which is mediated by Smads and FoxH1. Previous studies suggest that the suppression of Pitx2 gene in the left LPM is a potential cause of cardiac/laterality defects in Oculo-Facio-Cardio-Dental (OFCD) syndrome, which is known to be caused by mutations in BCL6 co-repressor (BCOR) gene. Recently, our work has revealed that the BCL6/BCOR complex blocks Notch-dependent transcriptional activity to protect the expression of Pitx2 in the left LPM from the inhibitory activity of Notch signaling. These studies indicated that uncontrolled Notch activity in the left LPM caused by dysfunction of BCOR may result in cardiac/laterality defects of OFCD syndrome. However, this Notch-dependent inhibitory mechanism of Pitx2 gene transcription still remains unknown. Here we report that transcriptional repressor ESR1, which acts downstream of Notch signaling, inhibits the expression of Pitx2 gene by binding to a left side-specific enhancer (ASE) region in Pitx2 gene and recruiting histone deacetylase 1 (HDAC1) to this region. Once HDAC1 is tethered, histone acetyltransferase p300 is no longer recruited to the Xnr1-dependent transcriptional complex on the ASE region, leading to the suppression of Pitx2 gene in the left LPM. The study presented here uncovers the regulatory mechanism of Pitx2 gene transcription which may contribute to an understanding of pathogenesis of OFCD syndrome.
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影响因子：
10.5
作者：
Chen, GQ;Fernandez, J;Courey, AJ
通讯作者：
Courey, AJ
影响因子：
4.6
作者：
Kageyama, Ryoichiro;Ohtsuka, Toshiyuki;Kobayashi, Taeko
通讯作者：
Kobayashi, Taeko
影响因子：
3.5
作者：
Hilton, Emma N.;Manson, Forbes D. C.;Black, Graeme C. M.
通讯作者：
Black, Graeme C. M.
DOI：
10.1038/ejhg.2009.52
发表时间：
2009-10
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
通讯作者：
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杂质基因galnt11糖基盐凹口策划纤毛类型和侧向。
影响因子：
64.8
作者：
通讯作者：
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