Prdm12 Is Induced by Retinoic Acid and Exhibits Anti-proliferative Properties through the Cell Cycle Modulation of P19 Embryonic Carcinoma Cells

Abstract

ABSTRACT. The Prdm (PRDI-BF1-RIZ1 homologous) family is involved in cell differentiation, and several Prdms have been reported to methylate histone H3 by intrinsic or extrinsic pathways. Here, we report that Prdm12 recruits G9a to methylate histone H3 on lysine 9 through its zinc finger domains. Because of the expression of Prdm12 in the developmental nervous system, we investigated the role of Prdm12 on P19 embryonic carcinoma cells as a model system for neurogenesis. In P19 cells, Prdm12 is induced by Retinoic acid (RA). Overproduction of Prdm12 in P19 cells impairs cell proliferation and increases the G1 population accompanied by the upregulation of p27. In contrast, the knockdown of Prdm12 increases the number of cells in a suspension culture of RA-induced neural differentiation. Both the PR domain and zinc finger domains are required for the anti-proliferative activity of Prdm12. While the data in this study is based on in vitro models, the results suggest that Prdm12 is induced by the RA signaling in vivo, and may regulate neural differentiation during animal development.

Prdm12 specifies V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes in Xenopus

“…As previously reported for the mouse protein (Yang and Shinkai, 2013), Xenopus Prdm12 exhibits histone methyltransferase activity.…”

“…We were further able to verify that lhx3 (lim3) and cyclin Dx (ccndx), which are expressed more ventrally, as well as neurog2 and sox3, which are expressed in undifferentiated neural cells, are indeed downregulated by Prdm12. Finally, we also tested p27Xic1 (cdknx), encoding a cyclin-dependent kinase inhibitory protein and the pan-neuronal differentiation marker N-tubulin as those genes were found upregulated by Prdm12 in P19 cells (Yang and Shinkai, 2013). Both of them were also upregulated by Prdm12 in our neuralized RA-treated caps.…”

“…To determine their functional contribution, we tested the activity of a series of mutants (Yang and Shinkai, 2013) in the chick neural tube (Fig. 5A).…”

“…Unlike other Prdm proteins, Prdm12 lacks direct histone methyltransferase activity and repress target gene expression by recruiting the methyltransferase G9a to dimethylate histone H3 at lysine 9 (H3K9me2) (Yang and Shinkai, 2013). Therefore, we asked whether G9a is necessary for Prdm12 function in the spinal cord.…”

“…In mouse and zebrafish embryos, Prdm12 is expressed in specific regions of the developing brain, in spinal cord p1 progenitors and in dorsal root and trigeminal ganglia (Kinameri et al, 2008). In P19 embryonic carcinoma cells, Prdm12 is induced by retinoic acid (RA) and inhibits cell proliferation (Yang and Shinkai, 2013). Recently, it has been shown that Prdm12 is required for V1 interneurons in zebrafish (Zannino et al, 2014).…”