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YTHDF2 destabilizes m(6)A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells

N(6)-methyladenosine (m(6)A) is an abundant post-transcriptional modification that can impact RNA fate via interactions with m(6)A-specific RNA binding proteins. Despite accumulating evidence that m(6)A plays an important role in modulating pluripotency, the influence of m(6)A reader proteins in plu...

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Detalles Bibliográficos
Autores principales: Heck, Adam M., Russo, Joseph, Wilusz, Jeffrey, Nishimura, Erin Osborne, Wilusz, Carol J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266156/
https://www.ncbi.nlm.nih.gov/pubmed/32169943
http://dx.doi.org/10.1261/rna.073502.119
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author Heck, Adam M.
Russo, Joseph
Wilusz, Jeffrey
Nishimura, Erin Osborne
Wilusz, Carol J.
author_facet Heck, Adam M.
Russo, Joseph
Wilusz, Jeffrey
Nishimura, Erin Osborne
Wilusz, Carol J.
author_sort Heck, Adam M.
collection PubMed
description N(6)-methyladenosine (m(6)A) is an abundant post-transcriptional modification that can impact RNA fate via interactions with m(6)A-specific RNA binding proteins. Despite accumulating evidence that m(6)A plays an important role in modulating pluripotency, the influence of m(6)A reader proteins in pluripotency is less clear. Here, we report that YTHDF2, an m(6)A reader associated with mRNA degradation, is highly expressed in induced pluripotent stem cells (iPSCs) and down-regulated during neural differentiation. Through RNA sequencing, we identified a group of m(6)A-modified transcripts associated with neural development that are directly regulated by YTDHF2. Depletion of YTHDF2 in iPSCs leads to stabilization of these transcripts, loss of pluripotency, and induction of neural-specific gene expression. Collectively, our results suggest YTHDF2 functions to restrain expression of neural-specific mRNAs in iPSCs and facilitate their rapid and coordinated up-regulation during neural induction. These effects are both achieved by destabilization of the targeted transcripts.
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spelling pubmed-72661562021-06-01 YTHDF2 destabilizes m(6)A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells Heck, Adam M. Russo, Joseph Wilusz, Jeffrey Nishimura, Erin Osborne Wilusz, Carol J. RNA Article N(6)-methyladenosine (m(6)A) is an abundant post-transcriptional modification that can impact RNA fate via interactions with m(6)A-specific RNA binding proteins. Despite accumulating evidence that m(6)A plays an important role in modulating pluripotency, the influence of m(6)A reader proteins in pluripotency is less clear. Here, we report that YTHDF2, an m(6)A reader associated with mRNA degradation, is highly expressed in induced pluripotent stem cells (iPSCs) and down-regulated during neural differentiation. Through RNA sequencing, we identified a group of m(6)A-modified transcripts associated with neural development that are directly regulated by YTDHF2. Depletion of YTHDF2 in iPSCs leads to stabilization of these transcripts, loss of pluripotency, and induction of neural-specific gene expression. Collectively, our results suggest YTHDF2 functions to restrain expression of neural-specific mRNAs in iPSCs and facilitate their rapid and coordinated up-regulation during neural induction. These effects are both achieved by destabilization of the targeted transcripts. Cold Spring Harbor Laboratory Press 2020-06 /pmc/articles/PMC7266156/ /pubmed/32169943 http://dx.doi.org/10.1261/rna.073502.119 Text en © 2020 Heck et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Article
Heck, Adam M.
Russo, Joseph
Wilusz, Jeffrey
Nishimura, Erin Osborne
Wilusz, Carol J.
YTHDF2 destabilizes m(6)A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells
title YTHDF2 destabilizes m(6)A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells
title_full YTHDF2 destabilizes m(6)A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells
title_fullStr YTHDF2 destabilizes m(6)A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells
title_full_unstemmed YTHDF2 destabilizes m(6)A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells
title_short YTHDF2 destabilizes m(6)A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells
title_sort ythdf2 destabilizes m(6)a-modified neural-specific rnas to restrain differentiation in induced pluripotent stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266156/
https://www.ncbi.nlm.nih.gov/pubmed/32169943
http://dx.doi.org/10.1261/rna.073502.119
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