Myeloid zinc finger 1 (Mzf1) differentially modulates murine cardiogenesis by interacting with an Nkx2.5 cardiac enhancer.
Myeloid zinc finger 1 (Mzf1) differentially modulates murine cardiogenesis by interacting with an Nkx2.5 cardiac enhancer.
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DOI：
10.1371/journal.pone.0113775
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Krane M
中科院分区：
文献类型：
--
作者：
Doppler SA;Werner A;Barz M;Lahm H;Deutsch MA;Dreßen M;Schiemann M;Voss B;Gregoire S;Kuppusamy R;Wu SM;Lange R;Krane M
脊椎动物心脏发育受生长因子和转录因子时空表达的严格调控。我们分析了9个TF，通过计算机分析Nkx2.5增强子选择，其反式激活各自的增强子元件的能力，特别是驱动心脏祖细胞（CPC）中基因的表达。Mzf 1在报告基因分析中显示出显著的活性，并在小鼠ES细胞分化过程中直接与Nkx2.5心脏增强子（Nkx2.5 CE）结合。虽然Mzf 1被确定为造血TF，但其调节心脏发生的能力完全未知。Mzf 1的表达显着丰富的CPC在体外分化的ES细胞和小鼠胚胎心脏。为了检测Mzf 1过表达对CPC形成的影响，我们产生了双转基因的、可诱导的tetOMzf 1-Nkx2.5 CE eGFP ES系。在体外分化过程中，早期和持续的Mzf 1过表达抑制CPC的形成和心脏基因的表达。晚期Mzf 1过表达，与Mzf 1表达的第二个生理高峰相一致，导致心脏发生增强。这些发现暗示了Mzf 1在胚胎心脏发育中的一种新颖的、时间特异性的作用。因此，我们在理解脊椎动物心脏发育和祖细胞分化的复杂机制方面增加了另一块拼图。因此，这方面的知识将是至关重要的，以指导有效的心脏再生策略，并获得进一步了解先天性心脏畸形的分子基础。
Vertebrate heart development is strictly regulated by temporal and spatial expression of growth and transcription factors (TFs). We analyzed nine TFs, selected by in silico analysis of an Nkx2.5 enhancer, for their ability to transactivate the respective enhancer element that drives, specifically, expression of genes in cardiac progenitor cells (CPCs). Mzf1 showed significant activity in reporter assays and bound directly to the Nkx2.5 cardiac enhancer (Nkx2.5 CE) during murine ES cell differentiation. While Mzf1 is established as a hematopoietic TF, its ability to regulate cardiogenesis is completely unknown. Mzf1 expression was significantly enriched in CPCs from in vitro differentiated ES cells and in mouse embryonic hearts. To examine the effect of Mzf1 overexpression on CPC formation, we generated a double transgenic, inducible, tetOMzf1-Nkx2.5 CE eGFP ES line. During in vitro differentiation an early and continuous Mzf1 overexpression inhibited CPC formation and cardiac gene expression. A late Mzf1 overexpression, coincident with a second physiological peak of Mzf1 expression, resulted in enhanced cardiogenesis. These findings implicate a novel, temporal-specific role of Mzf1 in embryonic heart development. Thereby we add another piece of puzzle in understanding the complex mechanisms of vertebrate cardiac development and progenitor cell differentiation. Consequently, this knowledge will be of critical importance to guide efficient cardiac regenerative strategies and to gain further insights into the molecular basis of congenital heart malformations.
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DOI：
10.1126/science.1177350
发表时间：
2009-10-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Domian IJ;Chiravuri M;van der Meer P;Feinberg AW;Shi X;Shao Y;Wu SM;Parker KK;Chien KR
通讯作者：
Chien KR
影响因子：
14.9
作者：
Chekmenev DS;Haid C;Kel AE
通讯作者：
Kel AE
影响因子：
23.9
作者：
Bondue, Antoine;Lapouge, Gaelle;Blanpain, Cedric
通讯作者：
Blanpain, Cedric
影响因子：
5.2
作者：
Mudduluru, Giridhar;Vajkoczy, Peter;Allgayer, Heike
通讯作者：
Allgayer, Heike
影响因子：
2.6
作者：
Ismailoglu, Ismail;Yeamans, Gabriel;Kyba, Michael
通讯作者：
Kyba, Michael