DNA methylation and SETDB1 /H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs.
|核心內(nèi)容：
DNA甲基化和組蛋白H3賴氨酸9三甲基化(H3K9me3)在基因和逆轉(zhuǎn)錄元件沉默中起著重要作用。（都是抑制性的表觀遺傳修飾）
Figure 1. SETDB1 and DNA Methylation Are Required for Silencing of Predominantly Distinct Sets of Genes.
然而，對(duì)這些途徑進(jìn)行抑制調(diào)控的基因和被抑制的重復(fù)元件的全面比較尚未見報(bào)道。 在這里，我們發(fā)現(xiàn)在小鼠胚胎干細(xì)胞(mESCs)中，在H3K9甲基轉(zhuǎn)移酶Setdb1
Figure 2. The Majority of SETDB1-Bound
Promoters Are Depleted of H3K9me3 in SETDB1 KO but Not DNMT TKO Cells
許多內(nèi)源性逆轉(zhuǎn)錄病毒(ERV)丟失H3K9me3，并伴隨著脫抑制，這個(gè)現(xiàn)象唯獨(dú)在 SETDB1 基因敲除的mESCs中出現(xiàn) 。（說明ERV特異性地受SETDB1 進(jìn)行H3K9me3 修飾，進(jìn)而被抑制）
Figure 3. Genes Depleted of Promoter
H3K9me3 in the SETDB1 KO Are Generally
Not Marked by DNA Methylation or
H3K27me3; (DNA Methylation or H3K27me3 也有管不到/抑制不了的基因，而這些基因需要SETDB1來加一個(gè)H3K9me3，進(jìn)而抑制該基因的表達(dá)）
值得注意的是，大約15%的上調(diào)基因是與啟動(dòng)子近端ERV的表達(dá)下調(diào)有關(guān)的，其中一半是在“嵌合”轉(zhuǎn)錄本的背景下誘導(dǎo)的，這些轉(zhuǎn)錄本起始于這些反轉(zhuǎn)錄元件并與基因外顯子拼接。
Figure 4. ERVs Are Derepressed in SETDB1
KO but Not DNMT TKO mESCs.
因此，SETDB1通過抑制近端ERV的表達(dá) ，在抑制異?；蜣D(zhuǎn)錄方面發(fā)揮了先前未被認(rèn)識(shí)但卻至關(guān)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 Is
Associated with Increased Expression of Promoter-Proximal ERVs
#基因組穩(wěn)定性的維持事關(guān)細(xì)胞本身的生死存亡，這么重要的事情不可能只需要DNA甲基化來抑制一些ERV內(nèi)賊，當(dāng)然也不可能只需要H3K9me3。它們都只是維持全基因組穩(wěn)定性的必要條件，但不是充分條件。#
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.
參考文獻(xiàn)：https:///10.1016/j.stem.2011.04.004
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