The Caenorhabditis elegans GATA factor ELT-1 works through the cell proliferation regulator BRO-1 and the Fusogen EFF-1 to maintain the seam stem-like fate.
The Caenorhabditis elegans GATA factor ELT-1 works through the cell proliferation regulator BRO-1 and the Fusogen EFF-1 to maintain the seam stem-like fate.
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DOI：
10.1371/journal.pgen.1002200
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发表时间：
2011-08
期刊：
影响因子：
4.5
通讯作者：
Woollard A
中科院分区：
文献类型：
--
作者：
Brabin C;Appleford PJ;Woollard A
秀丽线虫的缝隙细胞为干细胞的分裂模式提供了一个范例，具有自我更新和产生分化的子代的能力。转录因子RNT-1及其DNA结合伙伴BRO1(分别与哺乳动物癌症相关干细胞调节因子RUNX和CbFβ同源)是Seam细胞增殖的限速调节因子。在这里，我们结合比较基因组学和DNA结合分析表明，bro-1的表达直接受到GATA因子ELT-1的调节。ELT-1(RNAi)动物表现出与bro-1突变体相似的缝隙细胞谱系缺陷，但有一个额外的表型，即缝隙细胞失去干细胞样特性，并通过与th7表皮合胞体融合而不适当地分化。这种表型依赖于FusoGen EFF-1，我们发现它在Seam细胞中被ELT-1抑制。总体而言，我们的数据表明ELT-1在干细胞样缝细胞中具有双重作用，既促进增殖又防止分化。干细胞既能产生分化细胞，又能自我更新，产生更多的干细胞。在这些对立的选择之间做出选择对发展至关重要。在这里，我们使用Seam细胞作为干细胞分裂的模型，研究了线虫线虫这种选择背后的分子遗传学。转录因子RNT-1与BRO1(分别与哺乳动物RUNX和CBFβ基因同源)共同调控Seam细胞的增殖，反映了RUNX/CBFβ在哺乳动物干细胞中的作用。为了更好地了解bro-1是如何调控的，我们寻找了可能具有重要功能的非编码DNA的保守区域。我们确定了一个122bp保守的非编码元件，这是bro-1表达所必需的，也是充分的。随后的分析表明，GATA转录因子ELT-1直接调控bro-1。我们发现ELT-1实际上扮演着两个截然不同的角色，一方面促进缝隙细胞的增殖，另一方面也防止它们与周围组织不适当地融合，从而失去它们的干细胞样特性。此外，我们提出了干细胞特性的保留和缝隙细胞在不同隔室中的维持之间的联系，在这种隔间中，它们受到保护，不会分化。
Seam cells in Caenorhabditis elegans provide a paradigm for the stem cell mode of division, with the ability to both self-renew and produce daughters that differentiate. The transcription factor RNT-1 and its DNA binding partner BRO-1 (homologues of the mammalian cancer-associated stem cell regulators RUNX and CBFβ, respectively) are known rate-limiting regulators of seam cell proliferation. Here, we show, using a combination of comparative genomics and DNA binding assays, that bro-1 expression is directly regulated by the GATA factor ELT-1. elt-1(RNAi) animals display similar seam cell lineage defects to bro-1 mutants, but have an additional phenotype in which seam cells lose their stem cell-like properties and differentiate inappropriately by fusing with the hyp7 epidermal syncytium. This phenotype is dependent on the fusogen EFF-1, which we show is repressed by ELT-1 in seam cells. Overall, our data suggest that ELT-1 has dual roles in the stem-like seam cells, acting both to promote proliferation and prevent differentiation. Stem cells can both produce differentiated cells and self-renew, producing more stem cells. Choosing between these opposing options is critical for development. Here, we have investigated the molecular genetics underlying this choice in the nematode worm, C. elegans, using the seam cells as a model of stem cell divisions. The transcription factor RNT-1 works together with BRO-1 (homologues of mammalian RUNX and CBFβ genes, respectively) to regulate proliferation of the seam cells, reflecting the roles of RUNX/CBFβ in mammalian stem cells. To better understand how bro-1 is regulated, we looked for conserved regions of non-coding DNA, likely to be of functional importance. We identified a 122 bp conserved non-coding element that is necessary and sufficient for bro-1 expression. Subsequent analysis suggested that the GATA transcription factor ELT-1 directly regulates bro-1. We have found that ELT-1 actually performs two distinct roles, promoting proliferation of seam cells while also preventing them from inappropriately fusing with surrounding tissue and losing their stem-like properties. Furthermore, we propose a link between the retention of stem cell properties and the maintenance of seam cells in a distinct compartment, in which they are protected from differentiation.
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