Differential Roles of Sall4 Isoforms in Embryonic Stem Cell Pluripotency
Differential Roles of Sall4 Isoforms in Embryonic Stem Cell Pluripotency
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DOI：
10.1128/mcb.00419-10
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发表时间：
2010-11-01
影响因子：
5.3
通讯作者：
Orkin, Stuart H.
中科院分区：
文献类型：
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作者：
Rao, Sridhar;Zhen, Shao;Orkin, Stuart H.
小鼠胚胎干细胞（ES细胞）具有持续自我更新和多能性。由选择性剪接产生的多种蛋白质亚型在ES细胞中表达，但没有明确的生物学作用。Sall4是多能性所必需的转录因子，以两种同种型（Sall4a和Sall4b）存在。这两种异构体可以相互形成同源二聚体和异源二聚体，并且每一种都可以与Nanog相互作用。通过全基因组定位分析，我们确定Sall4a和Sall4b在ES细胞基因组内具有重叠但不相同的结合位点。此外，Sall4b而不是Sall4a优先结合ES细胞中的高表达基因座。Sall4a和Sall4b结合位点通过靶基因座处的表观遗传标记及其与其他多能性因子的结合位点的聚类来区分。当产生表达单一同种型Sall4的ES细胞时，单独的Sall4b可以维持多能状态，尽管它不能完全抑制所有分化标志物。Sall4a和Sall4b在维持多能状态方面合作，但发挥不同的作用。我们的工作是新的，在建立这样的同种型特异性差异的ES细胞。
Murine embryonic stem (ES) cells are defined by continuous self-renewal and pluripotency. A diverse repertoire of protein isoforms arising from alternative splicing is expressed in ES cells without defined biological roles. Sall4, a transcription factor essential for pluripotency, exists as two isoforms (Sall4a and Sall4b). Both isoforms can form homodimers and a heterodimer with each other, and each can interact with Nanog. By genomewide location analysis, we determined that Sall4a and Sall4b have overlapping, but not identical binding sites within the ES cell genome. In addition, Sall4b, but not Sall4a, binds preferentially to highly expressed loci in ES cells. Sall4a and Sall4b binding sites are distinguished by both epigenetic marks at target loci and their clustering with binding sites of other pluripotency factors. When ES cells expressing a single isoform of Sall4 are generated, Sall4b alone could maintain the pluripotent state, although it could not completely suppress all differentiation markers. Sall4a and Sall4b collaborate in maintenance of the pluripotent state but play distinct roles. Our work is novel in establishing such isoform-specific differences in ES cells.