The Wellcome Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Max Born Crescent, The King's Buildings, Edinburgh EH9 3BF, UK.
The Wellcome Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Max Born Crescent, The King's Buildings, Edinburgh EH9 3BF, UK; Informatics Forum, School of Informatics, University of Edinburgh, 10 Crichton Street, Edinburgh EH8 9AB, UK.
Mol Cell. 2021 Feb 18;81(4):845-858.e8. doi: 10.1016/j.molcel.2020.11.046. Epub 2021 Jan 5.
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 upregulated 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 (ESCs) and embryonic lethality in mice. In contrast, deletion of two other zinc-finger clusters was phenotypically neutral. Our data indicate that loss of pluripotency is triggered by downregulation of SALL4, leading to de-repression of a set of AT-rich genes that promotes neuronal differentiation. We conclude that base composition is not merely a passive byproduct of genome evolution and constitutes a signal that aids control of cell fate.
哺乳动物基因组包含具有独特 A/T 与 G/C 碱基对平均组成的长片段。在筛选可能通过结合富含 AT 基序来解释碱基组成的蛋白质的过程中，我们鉴定出了干细胞因子 SALL4，它含有多个锌指结构。负责与 AT 结合的结构域的突变极大地降低了 SALL4 基因组的占有率，并使基因按照其 AT 含量的比例提前上调。该单个 AT 结合锌指簇的失活模拟了 Sall4 缺失细胞中观察到的缺陷，包括胚胎干细胞 (ESC) 的过早分化和小鼠的胚胎致死。相比之下，缺失另外两个锌指簇在表型上是中性的。我们的数据表明，多能性的丧失是由 SALL4 的下调触发的，导致一组富含 AT 的基因的去抑制，从而促进神经元分化。我们得出结论，碱基组成不仅仅是基因组进化的一个被动副产物，而是构成了有助于控制细胞命运的信号。
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