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  GATA transcription factors drive initial Xist upregulation after fertilization through direct activation of a distal enhancer element

Ravid-Lustig, L., Sampath Kumar, A., Schwämmle, T., Dunkel, I., Noviello, G., Weigert, R., et al. (2022). GATA transcription factors drive initial Xist upregulation after fertilization through direct activation of a distal enhancer element. bioRxiv. doi:10.1101/2022.08.02.502458.

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Ravid-Lustig, Liat1, Author           
Sampath Kumar, Abhishek2, Author           
Schwämmle, Till1, Author           
Dunkel, Ilona1, Author           
Noviello, Gemma1, Author           
Weigert, Raha2, Author           
Pacini, Guido1, Author           
Buschow, Rene3, Author           
Ghauri, Afrah1, Author
Stötzel, Maximilian4, Author           
Wittler, Lars5, Author           
Meissner, Alexander2, Author           
Schulz, Edda G.1, Author           
Affiliations:
1Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2117286              
2Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
3Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              
4Stem Cell Chromatin (Aydan Bulut-Karslioglu), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014185              
5Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              

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 Abstract: To ensure dosage compensation for X-linked genes between the sexes, one X chromosome is
silenced during early embryonic development of female mammals. This process of
X-chromosome inactivation (XCI) is initiated through upregulation of the RNA Xist from one X
chromosome shortly after fertilization. Xist then mediates chromosome-wide gene silencing in
cis and remains expressed in all cell types except the germ line and the pluripotent state, where
XCI is reversed. The factors that drive Xist upregulation and thereby initiate XCI remain
however unknown. We identify GATA transcription factors as potent Xist activators and
demonstrate that they are essential for the activation of Xist in mice following fertilization.
Through a pooled CRISPR activation screen we find that GATA1 can drive ectopic Xist
expression in murine embryonic stem cells (mESCs). We demonstrate that all GATA factors can
activate Xist directly via a GATA-responsive regulatory element (RE79) positioned 100 kb
upstream of the Xist promoter. Additionally, GATA factors are essential for the induction of XCI in
mouse preimplantation embryos, as simultaneous deletion of three members of the GATA family
(GATA1/4/6) in mouse zygotes effectively prevents Xist upregulation. Thus, initiation of XCI and
possibly its maintenance in distinct lineages of the preimplantation embryo is ensured by the
combined activity of different GATA family members, and the absence of GATA factors in the
pluripotent state likely contributes to X reactivation. We thus describe a form of regulation in
which the combined action of numerous tissue-specific factors can achieve near-ubiquitous
expression of a target gene.

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Language(s): eng - English
 Dates: 2022-08-03
 Publication Status: Published online
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 Identifiers: DOI: 10.1101/2022.08.02.502458
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Title: bioRxiv
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