Student Tongji University, China (People's Republic)
Abstract: Human naïve pluripotent stem cells (PSCs), mirroring the in-vivo ground pluripotent state, exhibit plasticity and unbiased differentiation potential, capable of being induced into primed state PSCs or 8-cell(8c)-like cells. The N6-methyladenosine(m6A) modification has been identified as a pivotal regulator of cell fate, closely associated with the transcriptional programs governing totipotency in mouse embryonic stem cells. However, its specific impact on human pluripotency remains elusive. In this study we demonstrate that disrupting the function of METTL3 in human naïve PSCs, by knocking out or inhibiting METTL3, impedes the transition from the naïve state to the primed state, while fostering a shift towards an 8c-like state. METTL3 deficiency significantly boosts the expression and transcriptional activity of 8c-specific transcripts, elevates the proportion of 8c-like cells, and enhances their interspecies chimeric competency and their totipotency developmental potential. Additionally, METTL3 inhibition leads to a pronounced and rapid reduction in m6A levels. Interestingly, this reduction is not primarily observed in differentially expressed genes. Instead, it occurs predominantly in regulatory RNAs, including enhancer RNAs (eRNAs) and repeats, leading to increased chromatin accessibility. Overall, our findings suggest the potential regulatory role of m6A in the transcriptional programs transition between pluripotency and totipotency in human PSCs, underscoring the nuanced role of the epitranscriptome in human cell fate determination.
