Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development

In the developing brain, neural progenitor cells (NPCs) switch the differentiation competency via changing gene expression profiles that are governed partly by epigenetic control such as histone modification, although the precise mechanism is unknown. Here we found that ESET/Setdb1/KMT1E, a histone H3 Lys-9 (H3K9) methyltransferase, was highly expressed at early stages of brain development but down-regulated over time, and that ablation of ESET led to decreased H3K9 trimethylation and misregulation of genes, resulting in severe brain defects and early lethality. In the mutant brain, endogenous retrotransposons were derepressed, and non-neural gene expression was activated. Furthermore, early neurogenesis was most severely impaired, while astrocyte formation was enhanced. We conclude that there is an epigenetic role of ESET in temporal and tissue-specific gene regulation in the developing brain. We used microarrays to identify genes up- or down- regulated when ESET is ablated in the dorsal telencephalon. We used 3 WT and 3 cKO male E14.5 embryo for each analysis在发育中的大脑内，神经前体细胞（neural progenitor cells, NPCs）可通过改变基因表达谱切换分化潜能，此类基因表达谱的调控部分依赖于表观遗传调控（epigenetic control）与组蛋白修饰（histone modification）等机制，但其具体精准机制仍未明确。本研究发现，组蛋白H3赖氨酸9（histone H3 Lys-9, H3K9）甲基转移酶ESET/Setdb1/KMT1E在脑发育早期高表达，但随发育进程逐渐下调；敲除ESET会导致H3K9三甲基化水平降低以及基因表达失调，进而引发严重脑发育缺陷与早期致死。在ESET敲除的突变体大脑中，内源性逆转录转座子（endogenous retrotransposons）发生去抑制，非神经基因的表达被异常激活。此外，早期神经发生（neurogenesis）受到最为严重的损伤，而星形胶质细胞形成（astrocyte formation）则显著增强。综上，我们认为ESET在发育大脑的时序特异性与组织特异性基因调控中发挥表观遗传作用。为鉴定背侧端脑（dorsal telencephalon）中ESET被敲除后上调或下调的基因，我们采用基因芯片（microarrays）开展分析，每组实验均使用3只野生型（wild type, WT）与3只条件性敲除（conditional knockout, cKO）的雄性E14.5胚胎。