Abstract
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.
| Original language | English |
|---|---|
| Journal | Cell Death and Differentiation |
| DOIs | |
| Publication status | Accepted/In press - Jan 1 2019 |
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ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
A novel member of Prame family, Gm12794c, counteracts retinoic acid differentiation through the methyltransferase activity of PRC2. / 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.
In: Cell Death and Differentiation, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A novel member of Prame family, Gm12794c, counteracts retinoic acid differentiation through the methyltransferase activity of PRC2
AU - Napolitano, Giuliana
AU - Tagliaferri, Daniela
AU - Fusco, Salvatore
AU - Cirillo, Carmine
AU - De Martino, Ilaria
AU - Addeo, Martina
AU - Mazzone, Pellegrino
AU - Russo, Nicola Antonino
AU - Natale, Francesco
AU - Cardoso, Maria Cristina
AU - De Luca, Luciana
AU - Lamorte, Daniela
AU - La Rocca, Francesco
AU - De Felice, Mario
AU - Falco, Geppino
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85067315775&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067315775&partnerID=8YFLogxK
U2 - 10.1038/s41418-019-0359-9
DO - 10.1038/s41418-019-0359-9
M3 - Article
AN - SCOPUS:85067315775
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
ER -