Mammalian genomes contain long domains with distinct average compositions of A/T versus G/C base pairs. In a screen for proteins that might interpret base composition by binding to AT-rich motifs, we identified the stem cell factor SALL4 which contains multiple zinc-fingers. Mutation of the domain responsible for AT binding drastically reduced SALL4 genome occupancy and prematurely up-regulated genes in proportion to their AT content. Inactivation of this single AT-binding zinc-finger cluster mimicked defects seen in Sall4-null cells, including precocious differentiation of embryonic stem cells and embryonic le-thality in mice. In contrast, deletion of two other zinc-finger clusters was phenotypically neutral. Our data indicate that loss of pluripotency is triggered by down-regulation of SALL4, leading to de-repression of a set of AT-rich genes that promotes neuronal differ-entiation. We conclude that base composition is not merely a passive by-product of ge-nome evolution, but constitutes a signal that aids control of cell fate.

中文翻译：

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SALL4控制细胞命运以响应DNA碱基组成

哺乳动物基因组包含长域，其A / T与G / C碱基对的平均组成不同。在筛选可能通过结合AT丰富的基序来解释碱基组成的蛋白质的过程中，我们鉴定出了含有多个锌指的干细胞因子SALL4。负责AT结合的结构域突变会大大降低SALL4基因组的占有率，并根据其AT含量成比例地过早上调基因。单个AT结合锌指簇的失活模拟了在Sall4空细胞中观察到的缺陷，包括早熟分化胚胎干细胞和小鼠胚胎致死率。相反，其他两个锌指簇的缺失在表型上是中性的。我们的数据表明，多能性丧失是由SALL4的下调触发的，导致抑制一系列富含AT的基因，从而促进神经元分化。我们得出的结论是，基本组成不仅是基因组进化的被动副产物，而且还构成有助于控制细胞命运的信号。