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Targeted in vivo epigenome editing of H3K27me3

机译：H3K27me3的靶向体内表观基因组编辑

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Epigenetic modifications have a central role in transcriptional regulation. While several studies using next-generation sequencing have revealed genome-wide associations between epigenetic modifications and transcriptional states, a direct causal relationship at specific genomic loci has not been fully demonstrated, due to a lack of technology for targeted manipulation of epigenetic modifications. Recently, epigenome editing techniques based on the CRISPR-Cas9 system have been reported to directly manipulate specific modifications at precise genomic regions. However, the number of editable modifications as well as studies applying these techniques in vivo is still limited. Here, we report direct modification of the epigenome in medaka (Japanese killifish, Oryzias latipes) embryos. Specifically, we developed a method to ectopically induce the repressive histone modification, H3K27me3 in a locus-specific manner, using a fusion construct of Oryzias latipes H3K27 methyltransferase Ezh2 (olEzh2) and dCas9 (dCas9-olEzh2). Co-injection of dCas9-olEzh2 mRNA with single guide RNAs (sgRNAs) into one-cell-stage embryos induced specific H3K27me3 accumulation at the targeted loci and induced downregulation of gene expression. In this study, we established the in vivo epigenome editing of H3K27me3 using medaka embryos. The locus-specific manipulation of the epigenome in living organisms will lead to a previously inaccessible understanding of the role of epigenetic modifications in development and disease.
机译：表观遗传修饰在转录调控中具有核心作用。尽管使用下一代测序的几项研究揭示了表观遗传修饰和转录状态之间的全基因组关联，但由于缺乏靶向处理表观遗传修饰的技术，因此尚未完全证明特定基因组位点的直接因果关系。最近，据报道基于CRISPR-Cas9系统的表观基因组编辑技术可直接在精确的基因组区域操作特定的修饰。但是，可编辑修饰的数量以及在体内应用这些技术的研究仍然有限。在这里，我们报道了aka（日本embryo鱼，长嘴y）胚胎中表观基因组的直接修饰。具体而言，我们开发了一种方法，可以使用稻瘟病菌H3K27甲基转移酶Ezh2（olEzh2）和dCas9（dCas9-olEzh2）的融合构建体，以特定于基因座的方式异位诱导抑制性组蛋白修饰H3K27me3。将dCas9-olEzh2 mRNA与单向导RNA（sgRNA）共注射到一个细胞阶段的胚胎中会在目标基因座处引起特异性H3K27me3积累，并诱导基因表达的下调。在这项研究中，我们建立了使用medaka胚胎H3K27me3的体内表观基因组编辑。在生物体中表观基因组的基因座特异性操作将导致以前无法理解表观遗传修饰在发育和疾病中的作用。

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