A genome-wide screen reveals new regulators of the 2-cell-like cell state

Gupta, Nikhil; Yakhou, Lounis; Albert, Julien Richard; Azogui, Anaelle; Ferry, Laure; Kirsh, Olivier; Miura, Fumihito; Battault, Sarah; Yamaguchi, Kosuke; Laisné, Marthe; Domrane, Cécilia; Bonhomme, Frédéric; Sarkar, Arpita; Delagrange, Marine; Ducos, Bertrand; Cristofari, Gaël; Ito, Takashi; Greenberg, Maxim V. C.; Defossez, Pierre‐Antoine

doi:10.1038/s41594-023-01038-z

Cited by 4 publications

References 70 publications

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Comprendre la totipotence embryonnaire à partir des cellules 2C-like

Yakhou,

Azogui,

Therizols

et al. 2024

Med Sci (Paris)

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La totipotence est la capacité d’une cellule à générer un organisme entier, une propriété qui caractérise les premières cellules embryonnaires, comme le zygote et les blastomères. Dans cette revue, nous proposons une rétrospective des avancées réalisées au cours de la dernière décennie concernant l’étude de la totipotence avec, notamment, la découverte des cellules ES murines exprimant des marqueurs du stade 2-cellules (2CLC). Ce modèle a considérablement contribué à la meilleure compréhension des mécanismes moléculaires impliqués dans la totipotence (facteurs pionniers, régulation épigénétique, épissage, maturation nucléaire). Les cellules 2CLC ont aussi ouvert la voie au développement de nouveaux modèles cellulaires de totipotence humaine.

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Comprendre la totipotence embryonnaire à partir des cellules 2C-like

Yakhou,

Azogui,

Therizols

et al. 2024

Med Sci (Paris)

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A genetic screen identifies BEND3 as a regulator of bivalent gene expression and global DNA methylation

Yakhou,

Azogui,

Gupta

et al. 2023

Nucleic Acids Research

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Epigenetic mechanisms are essential to establish and safeguard cellular identities in mammals. They dynamically regulate the expression of genes, transposable elements and higher-order chromatin structures. Consequently, these chromatin marks are indispensable for mammalian development and alterations often lead to disease, such as cancer. Bivalent promoters are especially important during differentiation and development. Here we used a genetic screen to identify new regulators of a bivalent repressed gene. We identify BEND3 as a regulator of hundreds of bivalent promoters, some of which it represses, and some of which it activates. We show that BEND3 is recruited to a CpG-containg consensus site that is present in multiple copies in many bivalent promoters. Besides having direct effect on the promoters it binds, the loss of BEND3 leads to genome-wide gains of DNA methylation, which are especially marked at regions normally protected by the TET enzymes. DNA hydroxymethylation is reduced in Bend3 mutant cells, possibly as consequence of altered gene expression leading to diminished alpha-ketoglutarate production, thus lowering TET activity. Our results clarify the direct and indirect roles of an important chromatin regulator, BEND3, and, more broadly, they shed light on the regulation of bivalent promoters.

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Predicting Differentially Methylated Cytosines in TET and DNMT3 Knockout Mutants via a Large Language Model

Sereshki,

Lonardi

2024

Preprint

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DNA cytosine methylation is an epigenetic marker which regulates many cellular processes. Mammalian genomes typically maintain consistent methylation patterns over time, except in specific regulatory regions like promoters and certain types of enhancers. The dynamics of DNA methylation is controlled by a complex cellular machinery, in which the enzymes DNMT3 and TET play a major role. This study explores the identification of differentially methylated cytosines (DMCs) in TET and DNMT3 knockout mutants in mice and human embryonic stem cells. We investigate (i) whether a large language model can be trained to recognize DMCs from the sequence surrounding the cytosine of interest, (ii) whether a classifier trained on human knockout data can predict DMCs in the mouse genome (and vice versa), (iii) whether a classifier trained on DNMT3 knockout can predict DMCs for TET knockout (and vice versa). Our study identifies statistically significant motifs associated with the prediction of DMCs each mutant, shedding new light on the understanding of DNA methylation dynamics in stem cells. Our software tool is available at https://github.com/ucrbioinfo/dmc_prediction.

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A genome-wide screen reveals new regulators of the 2-cell-like cell state

Cited by 4 publications

References 70 publications

Comprendre la totipotence embryonnaire à partir des cellules 2C-like

Comprendre la totipotence embryonnaire à partir des cellules 2C-like

A genetic screen identifies BEND3 as a regulator of bivalent gene expression and global DNA methylation

Predicting Differentially Methylated Cytosines in TET and DNMT3 Knockout Mutants via a Large Language Model

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