KDM5B decommissions the H3K4 methylation landscape of self-renewal genes during trophoblast stem cell differentiation [ChIP-seq]

Trophoblast stem (TS) cells derived from the trophectoderm (TE) of mammalian embryos have the ability to self-renew indefinitely or differentiate into fetal lineages of the placenta. Epigenetic control of gene expression plays an instrumental role in dictating the fate of TS cell self-renewal and differentiation. However, the roles of histone demethylases and activating histone modifications such as methylation of histone 3 lysine 4 (H3K4me3/me2) in regulating TS cell expression programs, and in priming the epigenetic landscape for trophoblast differentiation, are largely unknown. Here, we demonstrate that the H3K4 demethylase, KDM5B, regulates the H3K4 methylome and expression landscapes of TS cells. Depletion of KDM5B resulted in downregulation of TS cell self-renewal genes and upregulation of trophoblast-lineage genes, which was accompanied by altered H3K4 methylation. Moreover, we found that KDM5B resets the H3K4 methylation landscape during differentiation in the absence of the external self-renewal signal, FGF4, by removing H3K4 methylation from promoters of self-renewal genes, and of genes whose expression is enriched in TS cells. Altogether, our data indicate an epigenetic role for KDM5B in regulating H3K4 methylation in TS cells and during trophoblast differentiation.

源自哺乳动物胚胎滋养外胚层（trophectoderm, TE）的滋养层干细胞（Trophoblast stem cells, TS cells）具备无限自我更新能力，亦可分化为胎盘的胎儿源性细胞谱系。基因表达的表观遗传调控在决定TS细胞自我更新与分化命运的过程中发挥关键作用。然而，组蛋白去甲基化酶（histone demethylases）以及激活型组蛋白修饰（activating histone modifications，例如组蛋白H3第4位赖氨酸甲基化（methylation of histone 3 lysine 4, H3K4me3/me2））在调控TS细胞表达程序、为滋养层分化预编程表观遗传景观中的作用，目前在很大程度上尚不明确。
本研究证实，H3K4去甲基化酶（H3K4 demethylase）KDM5B可调控TS细胞的H3K4甲基化组（H3K4 methylome）与表达谱（expression landscapes）。KDM5B缺失会导致TS细胞自我更新相关基因的表达下调，同时上调滋养层谱系相关基因的表达，该过程伴随H3K4甲基化模式的改变。此外，我们发现，在缺失外源性自我更新信号FGF4的分化过程中，KDM5B可通过清除自我更新基因启动子区域以及在TS细胞中高表达基因的启动子区域的H3K4甲基化，重置H3K4甲基化景观。
综上，本研究数据表明，KDM5B在TS细胞内以及滋养层分化过程中，通过调控H3K4甲基化发挥表观遗传调控功能。