H3K27ac Is Essential for Human Naive Pluripotency Modulated by m6A‐Driven EP300 Expression

Human pluripotent stem cells (hPSCs) can transition between primed and naive states, each defined by unique epigenetic features crucial for early human development. However, the precise regulatory mechanisms of these transitions, particularly involving the roles of H3K27ac and m6A modifications, remain unclear. Here, it is revealed that H3K27ac is essential for establishment of human naive pluripotency. This elevation is critical for maintaining the naive state, as inhibiting H3K27ac disrupts naive pluripotency, while enhancing it promotes the naive state. Furthermore, it is discovered that m6A, via the enzyme METTL3, indirectly controls H3K27ac by regulating EP300 expression, an enzyme involved in H3K27ac deposition. METTL3 overexpression suppresses EP300 protein, thereby reducing H3K27ac modification and impeding naive pluripotency. These findings uncover a novel interplay between H3K27ac and m6A, advancing the understanding of stem cell regulation. This work provides new insights into the epigenetic control of hPSCs, with potential implications for developmental biology and regenerative medicine.