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GATA 转录因子通过直接激活长距离增强子，在受精后驱动初始 Xist 的上调。

GATA transcription factors drive initial Xist upregulation after fertilization through direct activation of long-range enhancers.

机构信息

Systems Epigenetics, Otto Warburg Laboratories, Max Planck Institute for Molecular Genetics, Berlin, Germany.

Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.

出版信息

Nat Cell Biol. 2023 Nov;25(11):1704-1715. doi: 10.1038/s41556-023-01266-x. Epub 2023 Nov 6.

DOI:10.1038/s41556-023-01266-x
PMID:37932452
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10635832/
Abstract

X-chromosome inactivation (XCI) balances gene expression between the sexes in female mammals. Shortly after fertilization, upregulation of Xist RNA from one X chromosome initiates XCI, leading to chromosome-wide gene silencing. XCI is maintained in all cell types, except the germ line and the pluripotent state where XCI is reversed. The mechanisms triggering Xist upregulation have remained elusive. Here we identify GATA transcription factors as potent activators of Xist. Through a pooled CRISPR activation screen in murine embryonic stem cells, we demonstrate that GATA1, as well as other GATA transcription factors can drive ectopic Xist expression. Moreover, we describe GATA-responsive regulatory elements in the Xist locus bound by different GATA factors. Finally, we show that GATA factors are essential for XCI induction in mouse preimplantation embryos. Deletion of GATA1/4/6 or GATA-responsive Xist enhancers in mouse zygotes effectively prevents Xist upregulation. We propose that the activity or complete absence of various GATA family members controls initial Xist upregulation, XCI maintenance in extra-embryonic lineages and XCI reversal in the epiblast.

摘要

X 染色体失活（XCI）平衡了雌性哺乳动物中雌雄之间的基因表达。在受精后不久，来自一条 X 染色体的 Xist RNA 的上调启动了 XCI，导致染色体范围的基因沉默。XCI 在所有细胞类型中都被维持，除了生殖系和多能状态，在这些状态下 XCI 被逆转。触发 Xist 上调的机制仍然难以捉摸。在这里，我们将 GATA 转录因子鉴定为 Xist 的有效激活子。通过在鼠胚胎干细胞中的 pooled CRISPR 激活筛选，我们证明 GATA1 以及其他 GATA 转录因子可以驱动异位 Xist 表达。此外，我们描述了 Xist 基因座中的 GATA 反应性调节元件，这些元件被不同的 GATA 因子结合。最后，我们表明 GATA 因子对于小鼠胚胎植入前胚胎中 XCI 的诱导是必需的。在小鼠合子中缺失 GATA1/4/6 或 GATA 反应性 Xist 增强子可有效地阻止 Xist 的上调。我们提出，各种 GATA 家族成员的活性或完全缺失控制着初始 Xist 的上调、胚胎外谱系中的 XCI 维持以及内胚层中的 XCI 逆转。

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