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ARGONAUTE proteins regulate a specific network of genes through KLF4 in mouse embryonic stem cells

View ORCID ProfileMadlen Müller, View ORCID ProfileMoritz Schaefer, View ORCID ProfileTara Fäh, Daniel Spies, Rodrigo Peña-Hernández, View ORCID ProfileRaffaella Santoro, View ORCID ProfileConstance Ciaudo
doi: https://doi.org/10.1101/2021.10.18.464771
Madlen Müller
1Swiss Federal Institute of Technology Zurich, IMHS, Chair of RNAi and Genome Integrity, Zurich, Switzerland
2Life Science Zurich Graduate School, University of Zürich, Switzerland
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Moritz Schaefer
1Swiss Federal Institute of Technology Zurich, IMHS, Chair of RNAi and Genome Integrity, Zurich, Switzerland
2Life Science Zurich Graduate School, University of Zürich, Switzerland
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Tara Fäh
1Swiss Federal Institute of Technology Zurich, IMHS, Chair of RNAi and Genome Integrity, Zurich, Switzerland
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Daniel Spies
1Swiss Federal Institute of Technology Zurich, IMHS, Chair of RNAi and Genome Integrity, Zurich, Switzerland
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Rodrigo Peña-Hernández
3University of Zurich, Department of Molecular Mechanisms of Disease, Zurich, Switzerland
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Raffaella Santoro
3University of Zurich, Department of Molecular Mechanisms of Disease, Zurich, Switzerland
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Constance Ciaudo
1Swiss Federal Institute of Technology Zurich, IMHS, Chair of RNAi and Genome Integrity, Zurich, Switzerland
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  • For correspondence: cciaudo@ethz.ch
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ABSTRACT

The Argonaute proteins (AGO) are well-known for their essential role in post-transcriptional gene silencing in the microRNA (miRNA) biogenesis pathway. Only two AGOs (AGO1 and AGO2) are expressed in mouse embryonic stem cells (mESCs). The transcriptome of Ago mutant mESCs revealed a large and specific set of misregulated genes, compared to other miRNA biogenesis factor mutant cells, suggesting additional functions for the AGOs in stem cells. In this study, we endeavored to understand miRNA-independent roles of the AGOs in gene expression regulation through the integration of multiple datasets. Correlation of Ago mutant differential gene expression with ENCODE histone modification data of WT mESCs revealed that affected genes were regulated by the repressive histone modification H3K27me3. We validated this observation by performing chromatin immunoprecipitation followed by sequencing and observed a global loss of H3K27me3 in Ago mutant cells. Nevertheless, this reduction explains only a small part of the specific differential gene expression observed in Ago mutant mESCs. By integrating chromatin accessibility data in conjunction with prediction of transcription factor binding sites, we identified differential binding for five transcription factors, including KLF4 as a key modulator of more than half of the specific misregulation of gene expression in the absence of AGO proteins. Our findings illustrate that in addition to chromatin state, information about transcription factor binding is more revelatory in understanding the multi-layered mechanism adopted by cells to regulate gene expression. These data also highlight the importance of an integrative approach to unravel the variety of noncanonical functions of AGOs in mESCs.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 19, 2021.
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ARGONAUTE proteins regulate a specific network of genes through KLF4 in mouse embryonic stem cells
Madlen Müller, Moritz Schaefer, Tara Fäh, Daniel Spies, Rodrigo Peña-Hernández, Raffaella Santoro, Constance Ciaudo
bioRxiv 2021.10.18.464771; doi: https://doi.org/10.1101/2021.10.18.464771
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ARGONAUTE proteins regulate a specific network of genes through KLF4 in mouse embryonic stem cells
Madlen Müller, Moritz Schaefer, Tara Fäh, Daniel Spies, Rodrigo Peña-Hernández, Raffaella Santoro, Constance Ciaudo
bioRxiv 2021.10.18.464771; doi: https://doi.org/10.1101/2021.10.18.464771

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