Functional role of Tet-mediated RNA hydroxymethylcytosine in mouse ES cells and during differentiation

Jie Lan, Nicholas Rajan, Martin Bizet, Audrey Penning, Nitesh K. Singh, Diana Guallar, Emilie Calonne, Andrea Li Greci, Elise Bonvin, Rachel Deplus, Phillip J. Hsu, Sigrid Nachtergaele, Chengjie Ma, Renhua Song, Alejandro Fuentes-Iglesias, Bouchra Hassabi, Pascale Putmans, Frédérique Mies, Gerben Menschaert, Justin J. L. Wong, Jianlong Wang, Miguel Fidalgo, Bifeng Yuan and François Fuks ()
Additional contact information
Jie Lan: Université Libre de Bruxelles (ULB)
Nicholas Rajan: Université Libre de Bruxelles (ULB)
Martin Bizet: Université Libre de Bruxelles (ULB)
Audrey Penning: Université Libre de Bruxelles (ULB)
Nitesh K. Singh: Université Libre de Bruxelles (ULB)
Diana Guallar: CiMUS, Universidade de Santiago de Compostela–Health Research Institute (IDIS)
Emilie Calonne: Université Libre de Bruxelles (ULB)
Andrea Li Greci: Université Libre de Bruxelles (ULB)
Elise Bonvin: Université Libre de Bruxelles (ULB)
Rachel Deplus: Université Libre de Bruxelles (ULB)
Phillip J. Hsu: University of Chicago
Sigrid Nachtergaele: University of Chicago
Chengjie Ma: Wuhan University
Renhua Song: The University of Sydney
Alejandro Fuentes-Iglesias: CiMUS, Universidade de Santiago de Compostela–Health Research Institute (IDIS)
Bouchra Hassabi: Université Libre de Bruxelles (ULB)
Pascale Putmans: Université Libre de Bruxelles (ULB)
Frédérique Mies: Université Libre de Bruxelles (ULB)
Gerben Menschaert: Ghent University
Justin J. L. Wong: The University of Sydney
Jianlong Wang: Columbia University Irving Medical Center (CUIMC)
Miguel Fidalgo: CiMUS, Universidade de Santiago de Compostela–Health Research Institute (IDIS)
Bifeng Yuan: Wuhan University
François Fuks: Université Libre de Bruxelles (ULB)

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Tet-enzyme-mediated 5-hydroxymethylation of cytosines in DNA plays a crucial role in mouse embryonic stem cells (ESCs). In RNA also, 5-hydroxymethylcytosine (5hmC) has recently been evidenced, but its physiological roles are still largely unknown. Here we show the contribution and function of this mark in mouse ESCs and differentiating embryoid bodies. Transcriptome-wide mapping in ESCs reveals hundreds of messenger RNAs marked by 5hmC at sites characterized by a defined unique consensus sequence and particular features. During differentiation a large number of transcripts, including many encoding key pluripotency-related factors (such as Eed and Jarid2), show decreased cytosine hydroxymethylation. Using Tet-knockout ESCs, we find Tet enzymes to be partly responsible for deposition of 5hmC in mRNA. A transcriptome-wide search further reveals mRNA targets to which Tet1 and Tet2 bind, at sites showing a topology similar to that of 5hmC sites. Tet-mediated RNA hydroxymethylation is found to reduce the stability of crucial pluripotency-promoting transcripts. We propose that RNA cytosine 5-hydroxymethylation by Tets is a mark of transcriptome flexibility, inextricably linked to the balance between pluripotency and lineage commitment.

Date: 2020
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DOI: 10.1038/s41467-020-18729-6

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