ISL1 directly regulates FGF10 transcription during human cardiac outflow formation.
ISL1 directly regulates FGF10 transcription during human cardiac outflow formation.
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DOI：
10.1371/journal.pone.0030677
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Etchevers HC
中科院分区：
文献类型：
--
作者：
Golzio C;Havis E;Daubas P;Nuel G;Babarit C;Munnich A;Vekemans M;Zaffran S;Lyonnet S;Etchevers HC
LIM同源结构域基因Islet-1(Isl1)编码一种转录因子，该转录因子与人类心脏前体细胞的多能性有关，在小鼠中，第二心区(SHF)细胞能够正确部署成为心房、右室和流出道的心肌。已经确定了其他标记，以表征SHF的亚结构域，例如其前部区域的成纤维细胞生长因子Fgf10。虽然在许多脊椎动物中已经证明了它的重要作用的功能证据，但只有在一些模型中才显示出Isl1的SHF表达。我们在胚胎时间窗内研究了人Isl1和FGF10之间的关系，在此期间，线性心管重建为四个心室。ISL1转录界定了一个支持SHF在人类中保守存在的解剖区域，GATA家族的转录因子在其中共表达。同时，我们发现了一个新的增强子，在FGF10第一内含子中包含一个高度保守的IsL1共识结合位点。CHIP和EMSA证明了它被Isl1直接占领。在GATA4和TBX20心脏转录因子的存在下，ISL1介导的FGF10内含子元件的转录被增强。最后，转基因小鼠证实，内源性因素结合了人FGF10内含子增强子，以驱动发育中的心脏流出道中报告基因的表达。这些发现强调了在可能的情况下直接检查人类组织中的发育调控网络，以评估可能导致先天性畸形的候选非编码区的兴趣。
The LIM homeodomain gene Islet-1 (ISL1) encodes a transcription factor that has been associated with the multipotency of human cardiac progenitors, and in mice enables the correct deployment of second heart field (SHF) cells to become the myocardium of atria, right ventricle and outflow tract. Other markers have been identified that characterize subdomains of the SHF, such as the fibroblast growth factor Fgf10 in its anterior region. While functional evidence of its essential contribution has been demonstrated in many vertebrate species, SHF expression of Isl1 has been shown in only some models. We examined the relationship between human ISL1 and FGF10 within the embryonic time window during which the linear heart tube remodels into four chambers. ISL1 transcription demarcated an anatomical region supporting the conserved existence of a SHF in humans, and transcription factors of the GATA family were co-expressed therein. In conjunction, we identified a novel enhancer containing a highly conserved ISL1 consensus binding site within the FGF10 first intron. ChIP and EMSA demonstrated its direct occupation by ISL1. Transcription mediated by ISL1 from this FGF10 intronic element was enhanced by the presence of GATA4 and TBX20 cardiac transcription factors. Finally, transgenic mice confirmed that endogenous factors bound the human FGF10 intronic enhancer to drive reporter expression in the developing cardiac outflow tract. These findings highlight the interest of examining developmental regulatory networks directly in human tissues, when possible, to assess candidate non-coding regions that may be responsible for congenital malformations.
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