DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs.
|核心内容：
DNA甲基化和组蛋白H3赖氨酸9三甲基化(H3K9me3)在基因和逆转录元件沉默中起着重要作用。（都是抑制性的表观遗传修饰）
Figure 1. SETDB1 and DNA Methylation Are Required for Silencing of Predominantly Distinct Sets of Genes.
然而，对这些途径进行抑制调控的基因和被抑制的重复元件的全面比较尚未见报道。
在这里，我们发现在小鼠胚胎干细胞(mESCs)中，在H3K9甲基转移酶Setdb1缺失后上调的基因与在DNA甲基转移酶Dnmt1、DNMT3a和Dnmt3b缺失的mESCs中下调的基因不同，除了少数的主要是种系特异性的基因。（说明DNA甲基化抑制的基因和H3K9me3修饰的基因是不一样的）
Figure 2. The Majority of SETDB1-BoundPromoters Are Depleted of H3K9me3 in SETDB1 KO but Not DNMT TKO Cells
许多内源性逆转录病毒(ERV)丢失H3K9me3，并伴随着脱抑制，这个现象唯独在SETDB1基因敲除的mESCs中出现。（说明ERV特异性地受SETDB1进行H3K9me3修饰，进而被抑制）
Figure 3. Genes Depleted of PromoterH3K9me3 in the SETDB1 KO Are GenerallyNot Marked by DNA Methylation orH3K27me3; (DNA Methylation or H3K27me3 也有管不到/抑制不了的基因，而这些基因需要SETDB1来加一个H3K9me3，进而抑制该基因的表达）
值得注意的是，大约15%的上调基因是与启动子近端ERV的表达下调有关的，其中一半是在“嵌合”转录本的背景下诱导的，这些转录本起始于这些反转录元件并与基因外显子拼接。
Figure 4. ERVs Are Derepressed in SETDB1KO but Not DNMT TKO mESCs.
因此，SETDB1通过抑制近端ERV的表达，在抑制异常基因转录方面发挥了先前未被认识但却至关重要的作用。
Figure 5. Class I and II ERVs Are Simultaneously Derepressed and Lose H3K9me3 Exclusively in SETDB1 KO mESCs
Figure 6. Increased Genic Expression in SETDB1 KO mESCs IsAssociated with Increased Expression of Promoter-Proximal ERVs
#基因组稳定性的维持事关细胞本身的生死存亡，这么重要的事情不可能只需要DNA甲基化来抑制一些ERV内贼，当然也不可能只需要H3K9me3。它们都只是维持全基因组稳定性的必要条件，但不是充分条件。#
原文摘要：
DNA methylation and histone H3 lysine 9 trimethylation (H3K9me3) play important roles in silencing of genes and retroelements.
However, a comprehensive comparison of genes and repetitive elements repressed by these pathways has not been reported.
Here we show that in mouse embryonic stem cells (mESCs), the genes upregulated after deletion of the H3K9 methyltransferase Setdb1 are distinct from those derepressed in mESC deficient in the DNA methyltransferases Dnmt1, Dnmt3a, and Dnmt3b, with the exception of a small number of primarily germline-specific genes.
Numerous endogenous retroviruses (ERVs) lose H3K9me3 and are concomitantly derepressed exclusively in SETDB1 knockout mESCs.
Strikingly, ~15% of upregulated genes are induced in association with derepression of promoter-proximal ERVs, half in the context of "chimeric" transcripts that initiate within these retroelements and splice to genic exons.
Thus, SETDB1 plays a previously unappreciated yet critical role in inhibiting aberrant gene transcription by suppressing the expression of proximal ERVs.
参考文献：https://sci-hub.se/10.1016/j.stem.2011.04.004
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