Pramel7 mediates ground-state pluripotency through proteasomal-epigenetic combined pathways

Area of Science:

• Developmental Biology
• Epigenetics
• Stem Cell Biology

Background:

• Naive pluripotency is crucial for early embryonic development, established in the preimplantation epiblast.
• Embryonic stem cells (ESCs) model this naive pluripotency, with 2i culture conditions mimicking the developmental ground state via DNA hypomethylation and specific gene signatures.

Purpose of the Study:

• To investigate the role of Pramel7 (PRAME-like 7) in regulating DNA methylation and pluripotency in ESCs.
• To understand the mechanism by which Pramel7 influences UHRF1, a key DNA methylation maintenance factor.

Main Methods:

• Assessed Pramel7 expression in inner cell mass (ICM) and ESCs.
• Manipulated Pramel7 levels in serum-cultured ESCs to observe effects on gene expression, UHRF1 levels, and DNA methylation.
• Examined Pramel7 and UHRF1 expression dynamics in ICMs and Pramel7-knockout embryos.

Main Results:

• Pramel7 targets UHRF1 for proteasomal degradation, reducing DNA methylation maintenance.
• Increased Pramel7 expression in ESCs induced a preimplantation epiblast-like gene signature, decreased UHRF1, and caused global DNA hypomethylation.
• Pramel7 is essential for blastocyst formation, and its overexpression maintains ESC pluripotency; Pramel7 and UHRF1 show mutually exclusive expression in ICMs.

Conclusions:

• Pramel7 plays a critical role in regulating DNA methylation dynamics through proteasomal pathways.
• The Pramel7/UHRF1 axis is vital for establishing and maintaining the ground-state pluripotency characteristic of the preimplantation epiblast.
• Findings provide insights for optimizing in vitro ESC culture to better recapitulate in vivo developmental states.