- Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, Ben Haim MS, Eyal E, Yunger S, Pinto Y, Jaitin DA, Viukov S, Rais Y, Krupalnik V, Chomsky E, Zerbib M, Maza I, Rechavi Y, Massarwa R, Hanna S, Amit I, Levanon EY, Amariglio N, Stern-Ginossar N, Novershtern N, Rechavi G and Hanna JH.
m6A mRNA Methylation Facilitates Resolution of Naïve Pluripotency 9Toward Differentiation.
Science (2015) 347(6225):1002-1006. DOI: 10.1126/science.1261417 (60 citations)
- Preview: Stunnenberg GH, Vermeulen M & Atlasi Y. A Me6Age for pluripotency. Science 347 (6222):614-615 (2015).
- Preview: Zhao BS& He C. Fate by RNA methylation: m6A steers stem cell pluripotency. Genome Biology 16:43 (2015).
- Highlight: Sheppard TL. M6A partial differential. Nature Chemical Biology 11:175 (2015).
Summary and importance:
Our lab is deeply interested in epigenetic pathways regulating stem cell transitions. While the roles of epigenetic modifications on DNA or proteins (i.e. histones) continue to be extensively studied, the role of RNA modifications is only starting to be unveiled. There are more than 100 types of RNA epigenetic modifications, and m6A is the most abundant one on mRNA. The importance and function of m6A in mammalian development remained unclear until this study.
We identified Mettl3, an m6A writer, as a critical regulator for terminating naïve (inner-cell-mas-like) pluripotency and enabling differentiation, both in vitro and in vivo. Mettl3 knockout ESCs completely lack m6A in mRNAs and are viable. Yet, they fail to terminate the naïve pluripotent state, and subsequently undergo aberrant lineage priming at the post-implantation (primed) stage, leading to embryonic lethality. m6A predominantly restrains naïve pluripotency genes’ transcript stability, rather than translation efficiency. This study provided the first proof for critical importance of RNA epigenetics in mammalian development in vivo, and an indispensable role for m6A in pluripotent cell transitions.
Finally, we showed that distinct murine naïve and primed pluripotent states retain opposing dependence on a variety of epigenetic repressors (Mettl3, Dnmt1, Polycomb). Naïve ESCs tolerate loss of such repressors, while primed pluripotent cells are destabilized in response to the same manipulations. Thus, we identified for the first time multiple mechanisms that functionally regulate mouse naïve and primed pluripotency in an opposing manner. At the conceptual level, this work established the notion of naïve (inner-cell-mass-like) pluripotency as a unique “basal” synthesis with a minimal requirement for epigenetic repression.
We are currently using tolerance of human pluripotent cells to lack of such epigenetic repressors as a functional assay to evaluate and enhance several of the newly devised protocols to derive “mouse-like” naïve human pluripotent cells (Gafni et al. Nature 2013).