Pramel7 mediates naïve pluripotency through proteasomal-epigenetic combined pathways

Ground state naïve pluripotency is established in the inner cell mass (ICM) of the mature blastocyst and is present only transiently. Embryonic stem cells (ESCs) can be derived at this stage and represent the immortalization of the pluripotent state by acquiring the capacity for infinite self-renewal. The precise molecular changes accompanying the arrest of the normal developmental program during ICM/ESC transition remain to be fully elucidated. Compared to ESCs, naïve pluripotency of ICM has been associated with global DNA hypomethylation and a generally low repressive epigenetic state that might serve for a greater flexibility to undergo rapid and transient phenotypic and developmental changes. Here we show that Pramel7 (Preferentially Expressed Antigen in Melanoma-like 7), a protein exclusively expressed in ICM but present only at low levels in ESCs, functions as a substrate recognition component of the proteasome system by targeting degradation of UHRF1 (Ubiquitin-like, containing PHD and RING finger domains, 1), a key factor for the maintenance of DNA methylation. Enhancing the expression of Pramel7 in ESCs reduces UHRF1 levels, induces expression of ICM specific genes and causes global DNA hypomethylation. Expression of Pramel7 locks ESCs in pluripotency and destabilizes terminal differentiation by maintaining elevated expression of pluripotency genes through inhibition of de novo DNA methylation. Together, these findings reveal an as-yet-unappreciated dynamic nature of DNA methylation through the control of the proteasome pathway. Moreover, they offer important insights for the establishment of the unique epigenotype of naïve pluripotency that might help in establishing more physiological ESC culture conditions to in vitro reproduce the in vivo ground state pluripotency.