Identification of <i>Cdk8</i> and <i>Cdkn2d</i> as New Prame-Target Genes in 2C-like Embryonic Stem Cells.

Embryonic stem cells (ESCs) present a characteristic pluripotency heterogeneity correspondent to specific metastates. We recently demonstrated that retinoic acid (RA) induces an increase in a specific 2C-like metastate marked by target genes specific to the two-cell embryo stage in preimplantation. Prame (Preferentially expressed antigen in melanoma) is one of the principal actors of the pluripotency stage with a specific role in RA responsiveness. Additionally, PRAME is overexpressed in a variety of cancers, but its molecular functions are poorly understood. To further investigate Prame's downstream targets, we used a chromatin immunoprecipitation sequencing (ChIP-seq) assay in RA-enriched 2C-like metastates and identified two specific target genes, <i>Cdk8</i> and <i>Cdkn2d</i>, bound by Prame. These two targets, involved in cancer dedifferentiation and pluripotency, have been further validated in RA-resistant ESCs. Here, we observed for the first time that Prame controls the <i>Cdk8</i> and <i>Cdkn2d</i> genes in ESCs after RA treatment, shedding light on the regulatory network behind the establishment of naïve pluripotency.