Abstract
N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNA. In recent years, a slew of interesting studies had confirmed its essential role as a post-transcriptional regulator of gene expression in a wide range of biological processes, especially during development. However, the precise mechanism for m6A mediated regulation during early embryo development still remained incompletely clear, requiring further investigations. To address that issue, this PhD research program employed the mouse model to carry out in-depth investigation from two representative perspectives: pluripotency regulation and PGC specification. The first project found that m6A affects pluripotent states mainly by modulating signaling pathways. Immediate m6A depletion by Mettl3 knockdown promotes mESCs towards pluripotency exit. Follow-up live cell imaging analysis showed that mESCs with increased propensity towards pluripotency exit accumulate overtime. These effects depend on Fgf5 induced activation of both Erk and Akt pathways. Additional data also suggested that the impaired differentiation capacity caused by Mettl3 knockout might be a stable effect of m6A depletion. The second project demonstrated that m6A safeguards PGC lineage commitment via suppressing ERas-Akt pathway. m6A dependent decay of ERas mRNA restricts its expression and downstream Akt activity. The tightly controlled ERas-Akt pathway results in proper epigenetic resetting which ensures adequate number of intermediate cells competent for subsequent PGC specification. In summary, These findings uncover the critical role of signaling pathways in m6A mediated regulation during early embryogenesis. Besides, these results underline the importance of single cell approaches for dissecting complex biological effects. Most essentially, these two studies together with numerous future ones are laying out a conceptual foundation which may bring us closer to develop therapeutical approaches by targeting dynamic RNA modifications.
List of papers
Paper I. Jin KX, Zuo R, Anastassiadis K, Klungland A, Marr C, Filipczyk A. N6-methyladenosine (m6A) depletion regulates pluripotency exit by activating signaling pathways in embryonic stem cells. Proc Natl Acad Sci U S A. 2021 Dec 21;118(51): e2105192118. The paper is included in the thesis in DUO, and also available at: https://doi.org/10.1073/pnas.2105192118 |
Paper II. Rujuan Zuo, Kang-Xuan Jin, Ying Yao, Arne Klungland, Adam Filipczyk. (2021) N6- methyladenosine (m6A) restricts ERas safeguarding entry to the mouse germline. (Manuscript in preparation). To be published. The paper is removed from the thesis in DUO awaiting publishing. |