Digital Public Defence: Miaomiao Li

Master Miaomiao Li at Institute of Basic Medical Sciences will be defending the thesis “Novel Roles of the N6-methyladenosine Reader YTHDF2 in Genome Stability and Neuronal Development” for the degree of PhD (Philosophiae Doctor).

Photo: Qingfei Pan.

The trial lecture will be held as a video conference over Zoom.

The digital trial lecture will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.

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Digital Trial Lecture – time and place

See Digital Trial Lecture.

Adjudication committee

  • First opponent: Professor Yang Shi, Harvard Medical School, Blavatnik Institute for Cell Biology and Boston Children's Hospital
  • Second opponent: Group leader Eva Maria Novoa Pardo, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology
  • Third member and chair of the evaluation committee: Associate Professor Ragnhild Eskeland, University of Oslo

Chair of the Defence

Professor Ludvig Magne Sollid, University of Oslo

Principal Supervisor

Professor II Arne Klungland, University of Oslo

Summary

The interest in modifications in RNA has increased dramatically following the initial studies on the reversible nature of m6A in mRNA and the ability to characterize the transcriptome-wide distribution by antibodies raised against m6A. A few years later, the first protein binding to m6A in mRNA, YTHDF2, was identified. We found loss of Ythdf2 globally caused embryonic lethality characterized by compromised neural development. We first comprehensively analyzed the neural defects of Ythdf2 knockout mice and found that the asymmetric division of apical progenitor cells was disturbed, which led to fewer basal progenitor cells being generated. Our Ythdf2 targeted mice also became valuable for studies to gain insight on how Ythdf2 deletion might lead to embryonic lethality and disrupted brain development. In cytoplasma, YTHDF2 depletion caused the retention of m6A-modified transcripts in Ythdf2 knockout neurospheres, leading to increased m6A enrichment. We proposed that erroneous recognition and degradation of m6A containing mRNA at this stage led to the dysregulation of neural development. In collaboration with the University of Nottingham, we found that YTHDF2 also locates to the nucleus and exhibits a high degree of co-localization with RNA:DNA hybrids in interphase cells. This completely new function of YTHDF2 in regulating R-loop stability could well explain the lethality of Ythdf2-targeted mice. The role of m6A in regulating R-loop stability will lead to numerous studies to unravel its potential role in chromosome stability. Increased R-loops-associated DNA damage, with a large increase in γH2AX staining, indicates genomic stability is associated with Ythdf2 deletion. Our ongoing work tries to investigate whether R-loop helicases (DDX3X) coordinate with m6A readers (YTHDF2) to regulate transcription and genomic stability.

 

Additional information

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Published Sep. 14, 2020 10:59 AM - Last modified Sep. 18, 2020 2:32 PM