N6-methyladenosine (m <sup>6</sup> A) depletion regulates pluripotency exit by activating signaling pathways in embryonic stem cells
Kang-Xuan Jin, Ru-Juan Zuo, Konstantinos Anastassiadis, Arne Klungland, Carsten Marr, Adam Filipczyk
Abstract
Significance Dynamic deposition of the N6-methyladenosine (m 6 A) modification on messenger RNA (mRNA) regulates pluripotency in embryonic stem cells. Reports show that depletion of m 6 A abundances increases the mRNA stability of pluripotency and lineage transcription factors (TFs) alike. If the mRNAs of these two TF groups become stabilized, it remains unclear how the pluripotency or lineage commitment decision is implemented. Quantification of pluripotency TFs live at single-cell resolution over generations shows long-term preservation of both pluripotency and priming. m 6 A depletion activates key signaling pathways involved in pluripotency versus commitment decisions. This occurs independently of m 6 A control over TF mRNA transcript stability. m 6 A deposition regulates TF protein expression levels by activating pErk and pAkt signaling to enact cell-fate determination in pluripotent stem cells.