A novel member of Prame family, Gm12794c, counteracts retinoic acid differentiation through the methyltransferase activity of PRC2

Embryonic stem cells (ESCs) fluctuate among different levels of pluripotency defined as metastates. Sporadically, metastable cellular populations convert to a highly pluripotent metastate that resembles the preimplantation two-cell embryos stage (defined as 2C stage) in terms of transcriptome, DNA m...

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Bibliographic Details
Published in:Cell death and differentiation 2020-01, Vol.27 (1), p.345-362
Main Authors: Napolitano, Giuliana, Tagliaferri, Daniela, Fusco, Salvatore, Cirillo, Carmine, De Martino, Ilaria, Addeo, Martina, Mazzone, Pellegrino, Russo, Nicola Antonino, Natale, Francesco, Cardoso, Maria Cristina, De Luca, Luciana, Lamorte, Daniela, La Rocca, Francesco, De Felice, Mario, Falco, Geppino
Format: Article
Language:English
Subjects:
Acetylation
Amino Acid Motifs
Animals
Cell Differentiation - drug effects
Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis
Cyclin-Dependent Kinase Inhibitor p21 - genetics
DNA Methylation
Embryonic Stem Cells - cytology
Embryonic Stem Cells - drug effects
Embryonic Stem Cells - enzymology
Embryonic Stem Cells - metabolism
Gene expression
Gene Knock-In Techniques
Histones - metabolism
Leucine-Rich Repeat Proteins
Methyltransferase
Mice
Multigene Family
NIH 3T3 Cells
Phylogeny
Polycomb Repressive Complex 2 - metabolism
Polycomb Repressive Complex 2 - physiology
Proteins - chemistry
Proteins - classification
Proteins - genetics
Proteins - physiology
Retinoic acid
Signal Transduction
Stem cells
Transcription, Genetic
Tretinoin - pharmacology
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Summary:Embryonic stem cells (ESCs) fluctuate among different levels of pluripotency defined as metastates. Sporadically, metastable cellular populations convert to a highly pluripotent metastate that resembles the preimplantation two-cell embryos stage (defined as 2C stage) in terms of transcriptome, DNA methylation, and chromatin structure. Recently, we found that the retinoic acid (RA) signaling leads to a robust increase of cells specifically expressing 2C genes, such as members of the Prame family. Here, we show that Gm12794c, one of the most highly upregulated Prame members, and previously identified as a key player for the maintenance of pluripotency, has a functional role in conferring ESCs resistance to RA signaling. In particular, RA-dependent expression of Gm12794c induces a ground state-like metastate, as evaluated by activation of 2C-specific genes, global DNA hypomethylation and rearrangement of chromatin similar to that observed in naive totipotent preimplantation epiblast cells and 2C-like cells. Mechanistically, we demonstrated that Gm12794c inhibits Cdkn1A gene expression through the polycomb repressive complex 2 (PRC2) histone methyltransferase activity. Collectively, our data highlight a molecular mechanism employed by ESCs to counteract retinoic acid differentiation stimuli and contribute to shed light on the molecular mechanisms at grounds of ESCs naive pluripotency-state maintenance.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-019-0359-9