N 6 -Methyladenosine Safeguards Mouse and Human Germline Competence

Le résumé fourni par la source

N 6 -Methyladenosine (m 6 A) regulation of germline entry in post-implantation-like-pluripotent states remains poorly defined. We characterized m 6 A depletion by Mettl3 or Mettl14 knock-down or METTL3 inhibition in in vitro models enabling primordial germ-cell-like-cell and somatic differentiation. Upon m 6 A depletion, mouse epiblast-like cells upregulated embryonic Ras (Eras) and PI3K-pAKT, facilitating EZH2 repression and depletion of H3K27me3. Consequently, enhancer activation promoted global gene deregulation and impaired germline entry. In mouse formative stem cells, ERAS-PI3K-pAKT upregulation resulted in unscheduled Blimp1 and Otx2 co-expression, germline entry deficiency and enhanced mesodermal differentiation. Conversely, upon m 6 A depletion, germline competent human pluripotent stem cells upregulated OTX2 through FGF-pERK activation, resulting in germline entry deficiency and enhanced neuroectodermal differentiation. meRIP-seq revealed preferential m 6 A deposition on mouse mesodermal and human neuroectodermal transcripts, suggesting a basis for differentiation bias following m 6 A depletion. We illustrate how decreasing m 6 A abundances impact signaling, chromatin epigenetics and transcript stabilities, constituting a powerful cell intrinsic barrier for germline entry.

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