Characterisation of the role of Mettl3-mediated m6A methylation in skeletal muscle cells
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Philipps-Universität Marburg
Abstract
A growing body of evidence suggests a pivotal role of N6-Methyladenosine
(m6A) modifications for biological processes, including stem cell differentiation. While
initial steps have been taken to explore the influence of m6A on muscle stem cell
(MuSC) development, several open questions remain, including contradictory findings
about the regulation of MuSCs by m6A. These include dual effects of METTL3 on
proliferation and differentiation, identification of direct m6A targets, underlying
mechanisms, and the roles of (non-)canonical m6A binding proteins.
My research focused on the function of Mettl3-mediated m6A modifications for skeletal
muscle cell development and regeneration, revealing effects of m6A on proliferation
and differentiation of MuSCs. My study revealed the requirement of Mettl3 in Pax7-
positive MuSCs for efficient muscle cell differentiation. Furthermore, several potential
direct m6A targets were identified, including COUP-TFII (Nr2f2), a transcription factor
involved in the pathogenesis of Duchenne muscular dystrophy.
My investigations highlight the role of m6A in the metabolism of Ribonucleic acids
(RNAs), particularly RNA stability and translation. It demonstrates that Mettl3 strongly
influences mRNA degradation and splicing, disclosing that genes differentially
expressed in m6A-deficient MuSCs often show changes in the splicing patterns. The
study also examines m6A proteins that interact with m6A-modified RNAs and
demonstrates the existence of non-canonical m6A readers.
Novel methodologies such as GLORI-Sequencing were established and applied to
muscle cells for improving detection of m6A and enabling stoichiometric identification
of m6A sites at single nucleotide resolution. Complex m6A methylation patterns were
mapped, and their interplay with RNA G-quadruplexes (RG4s) were explored,
suggesting links between RG4s and epitranscriptomic changes.
In conclusion, my research answers several questions about the function of m6A-
dependent processes in muscle stem cell development. The identification of direct
targets, mechanisms, and interactions improves understanding of the role of
epitranscriptomics for critical cellular activities
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