Abstract
Trophoblast stem cell (TSC) is crucial to the formation of placenta in mammals. Histone demethylase JMJD2 (also known as KDM4) family proteins have been previously shown to support self-renewal and differentiation of stem cells. However, their roles in the context of the trophoblast lineage remain unclear. Here, we find that knockdown of Jmjd2b resulted in differentiation of TSCs, suggesting an indispensable role of JMJD2B/KDM4B in maintaining the stemness. Through the integration of transcriptome and ChIP-seq profiling data, we show that JMJD2B is associated with a loss of H3K36me3 in a subset of embryonic lineage genes which are marked by H3K9me3 for stable repression. By characterizing the JMJD2B binding motifs and other transcription factor binding datasets, we discover that JMJD2B forms a protein complex with AP-2 family transcription factor TFAP2C and histone demethylase LSD1. The JMJD2B–TFAP2C–LSD1 complex predominantly occupies active gene promoters, whereas the TFAP2C–LSD1 complex is located at putative enhancers, suggesting that these proteins mediate enhancer–promoter interaction for gene regulation. We conclude that JMJD2B is vital to the TSC transcriptional program and safeguards the trophoblast cell fate via distinctive protein interactors and epigenetic targets.
Highlights
Placenta is an essential organ for fetal growth in mammals, providing an interface for the exchange of nutrients, oxygen, metabolites and other molecules between the fetal and maternal bloodstream
To ask whether the JMJD2 family is essential in Trophoblast stem cell (TSC), we treated TSCs with JIB-04, which is a non-competitive inhibitor of α-ketoglutarate and serves as a pan-selective inhibitor of Jumonji histone demethylases, including KDM5/JARID1 family, KDM4/JMJD2 family, and KDM6B/JMJD324–26
It was observed that stemness-associated genes, including Cdx[2], Eomes, and Elf[5], were significantly downregulated by 2.5–3.5 folds at 50 nM JIB-04 treatment for 48 h, and their expressions were further decreased at 100 nM treatment in a dosage-dependent manner (Fig. 1a)
Summary
Placenta is an essential organ for fetal growth in mammals, providing an interface for the exchange of nutrients, oxygen, metabolites and other molecules between the fetal and maternal bloodstream. The differential DNA methylation of transcription factor Elf[5] was proposed to be responsible for safeguarding the commitment of trophoblast cell fate in TSCs. the restricted expression of other key trophoblast stemness genes, such as Cdx[2] and Eomes, was not regulated by DNA methylation in both ESCs and T SCs11, suggesting the involvement of other epigenetic mechanisms in trophoblast lineage specification and maintenance. Several studies using ESC models demonstrated the binding of JMJD2 proteins at trophoblast lineage gene loci, such as Cdx[2], Eomes, Tfap2c, Hand[1], Ovol[2], and Gcm[119,22,23], suggesting a repressive role of JMJD2 to the trophoblast cell fate in ESCs. Whether JMJD2 family is epigenetically involved in the maintenance of stemness in TSCs remains to be elucidated. Our data reveal that JMJD2B regulates the transcriptional program via distinctive interacting partners and epigenetic mechanisms that are crucial to the lineage identity of TSCs
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