Poster Presentation 41st Lorne Genome Conference 2020

Roles of 5-Methylcytosine (m5C) RNA modification in embryonic stem cells (#116)

Michael Bullen 1 , Yogesh Kumar 1 , Varun Pandey 1 , Effie Apostolou 2 , Ryan Lister 3 , Eric Miska 4 , Leighton Core 5 , Pratibha Tripathi 1 , Partha Pratim Das 1
  1. Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
  2. Division of Hematology & Medical Oncology, Weill Cornell Medicine , New York, NY, USA
  3. The Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia
  4. The Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, UK
  5. Department of Molecular and Cell Biology, Institute of Systems Genomics, University of Connecticut, Connecticut, USA

Epitranscriptomic or RNA epigenetic modifications take place at the post-transcriptional level in transcribed RNAs without altering any RNA nucleotides/nucleosides. Until now, over 150 different types of RNA modifications have been identified in a range of different classes of RNAs, in various organisms ranging from yeast to mammals. However, recent advancement in high throughput sequencing technology can able to map only a few of these modifications transcriptome-wide in a precise manner that enables to understand the molecular and biological functions of the RNA modifications. To date, METTL3 (an m6A- methyltransferase) and its associated factor (ZC3H13) have been shown to play an important role in embryonic stem cells (ESCs). However, roles of other RNA modifications including, 5-methylcytosine (m5C) is currently unexplored in ESCs. In this study, we focused on m5C RNA modification that is catalysed by m5C methyltransferases (m5C writers) – TRDMT1 and NSUN1-7. These m5C writers mostly methylate tRNAs, rRNAs, mitochondrial RNAs. Only NSUN2 (the best-studied m5C methyltransferase) has been found to methylate a small number of mRNAs. To investigate the detailed functions of m5C in ESCs, we generated the Nsun2 KO in mouse ESCs (mESCs) using CRISPR-Cas9 that display self-renewal defects. Subsequent molecular analyses using RNA-seq (transcriptomic), m5c BS RNA-seq (epitranscriptomic) and PRO-seq (detects nascent transcripts) reveal “multidimensional” functions of NSUN2 through “transcriptional” and/or “post-transcriptional” regulation of maternal Meg3, Rian, Mirg long non-coding RNAs (from the Dlk1-Dio3 imprinted locus), c-Myc, Dicer-1, and Ccnd-1,2 that ultimately control self-renewal of the mESCs. Thus, our findings uncover the novel function of NSUN2, which orchestrates multidimensional gene regulatory functions to control self-renewal for the maintenance of mESC state.