Mus musculus Genome sequencing and assembly and Transcriptomics

SETDB1 is a key lysine methyltransferase (KMT) required in embryonic stem cells (ESCs), where it silences transposable elements and DNA repeats via histone H3 lysine 9 tri-methylation (H3K9me3), independently of DNA methylation. The H3K9 methylation reader M-Phase Phosphoprotein 8 (MPP8) is highly expressed ESCs and germline cells. Although evidence of cooperation between H3K9 KMTs and MPP8 in committed cells has emerged, the interplay between H3K9 methylation writers and MPP8 in ESCs remains elusive. Here, we show that MPP8 interacts physically and functionally with SETDB1 in ESCs. Indeed, combining biochemical, transcriptomic and genomic analyses, we found that MPP8 and SETDB1 co-regulate a significant number of common genomic targets, especially the DNA satellite repeats. Together, our data point to a model in which the silencing of a class of repeated sequences in ESCs involves the cooperation between the H3K9 methylation writer SETDB1 and its reader MPP8.

SETDB1是一种关键的赖氨酸甲基转移酶（lysine methyltransferase, KMT），在胚胎干细胞（embryonic stem cells, ESCs）中发挥必需功能。其可通过组蛋白H3赖氨酸9三甲基化（histone H3 lysine 9 tri-methylation, H3K9me3）沉默转座因子与DNA重复序列，且该调控过程不依赖DNA甲基化。H3K9甲基化阅读器——有丝分裂期磷酸化蛋白8（MPP8）在胚胎干细胞与生殖系细胞中呈高表达水平。尽管已有研究证实H3K9 KMT与MPP8在定型细胞中存在协同作用，但胚胎干细胞内H3K9甲基化写入因子与MPP8的相互调控机制仍不明确。本研究证实，MPP8在胚胎干细胞中可与SETDB1发生物理与功能层面的相互作用。通过联合生化、转录组学与基因组学分析，我们发现MPP8与SETDB1共同调控大量共有基因组靶标，其中尤以DNA卫星重复序列为甚。综上，本研究数据支持如下模型：胚胎干细胞中一类重复序列的沉默过程，依赖于H3K9甲基化写入因子SETDB1与其阅读器MPP8的协同作用。