德国马克斯·普朗克分子遗传学研究所Edda G. Schulz团队发现，GATA转录因子通过直接激活长程增强子驱动受精后Xist的初始上调。相关论文于2023年11月6日在线发表在《自然—细胞生物学》杂志上。

研究人员发现，GATA转录因子是Xist的强效激活因子。通过在小鼠胚胎干细胞中进行CRISPR激活筛选，研究人员证明GATA1和其他GATA转录因子可以驱动Xist的异位表达。此外，研究人员还描述了Xist基因座中由不同GATA因子结合的GATA响应调控元件。最后，研究人员证明GATA因子对小鼠植入前胚胎中的X染色体失活（XCI）诱导至关重要。在小鼠胚胎中删除GATA1/4/6或GATA响应的Xist增强子可有效阻止Xist的上调。研究人员认为，各种GATA家族成员的活性或完全缺失控制着最初的Xist上调、胚外系的XCI维持以及上胚层的XCI逆转。

据介绍，XCI平衡了雌性哺乳动物两性之间的基因表达。受精后不久，来自一条X染色体的Xist RNA的上调启动了XCI，导致整个染色体的基因沉默。XCI在所有细胞类型中都能维持，但生殖系和多能状态除外，在多能状态中，XCI会发生逆转。引发Xist上调的机制一直难以捉摸。

附：英文原文

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

Author: Ravid Lustig, Liat, Sampath Kumar, Abhishek, Schwmmle, Till, Dunkel, Ilona, Noviello, Gemma, Limberg, Elodie, Weigert, Raha, Pacini, Guido, Buschow, Ren, Ghauri, Afrah, Sttzel, Maximilian, Wittler, Lars, Meissner, Alexander, Schulz, Edda G.

Issue&Volume: 2023-11-06

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. Through a CRISPR-activation screen, Ravid Lustig et al. show that GATA transcription factors activate long-range Xist enhancers to upregulate Xist expression and initiate X chromosome inactivation in early mouse embryos.

DOI: 10.1038/s41556-023-01266-x

Source: https://www.nature.com/articles/s41556-023-01266-x