Switching roles for DNA and histone methylation depend on evolutionary ages of human endogenous retroviruses.
Switching roles for DNA and histone methylation depend on evolutionary ages of human endogenous retroviruses.
复制标题
DOI：
10.1101/gr.234229.118
复制
发表时间：
2018-08
期刊：
影响因子：
7
通讯作者：
Jones PA
中科院分区：
文献类型：
--
作者：
Ohtani H;Liu M;Zhou W;Liang G;Jones PA
我们提供了一个全面的基因组和表观基因组图超过500,000内源性逆转录病毒（erv）和片段，填充人类基因组的基因间区域。与erv相关的抑制表观遗传标记，特别是长末端重复序列（LTRs），显示出沉默机制的显著改变，这取决于LTRs的进化年龄。年轻的ltr往往富含CpG，主要受DNA甲基化抑制，而中年ltr主要与组蛋白修饰有关，特别是组蛋白H3赖氨酸9 （H3K9）甲基化。单独用DNA甲基化抑制剂5-aza-2 ' -脱氧胞苷（5-aza-CdR）处理可以重新激活年轻的LTRs，但如果5-aza-CdR处理加上敲除几种H3K9甲基转移酶之一或H3K27甲基转移酶EZH2，它们的表达水平会大大增加。胞嘧啶甲基化的去除导致ltr中H3K9me3快速、广泛地增加。中等年龄LTRs的CpG密度较低，且未被5-aza-CdR上调，但它们对H3K9甲基转移酶的下调敏感。与胚胎干细胞的情况不同，多梳抑制复合体（PRC2）本身在LTR抑制中起次要作用，并且在所分析的癌细胞系中仅在胞嘧啶甲基化去除后才发挥作用。ltr的上调和诱导“病毒模仿”正迅速成为预测癌症患者对表观遗传治疗反应的兴趣。了解LTR抑制的机制对于改善患者的治疗策略具有重要意义。
We provide a comprehensive genomic and epigenomic map of the more than 500,000 endogenous retroviruses (ERVs) and fragments that populate the intergenic regions of the human genome. The repressive epigenetic marks associated with the ERVs, particularly long terminal repeats (LTRs), show a remarkable switch in silencing mechanisms, depending on the evolutionary age of the LTRs. Young LTRs tend to be CpG rich and are mainly suppressed by DNA methylation, whereas intermediate age LTRs are associated predominantly with histone modifications, particularly histone H3 lysine 9 (H3K9) methylation. Young LTRs can be reactivated by treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-aza-CdR) alone, but their level of expression is much increased by 5-aza-CdR treatment plus knockdown of one of several H3K9 methyltransferases or of the H3K27 methyltransferase EZH2. The removal of cytosine methylation led to rapid, widespread increases in H3K9me3 in the LTRs. Intermediate age LTRs had lower CpG densities and were not up-regulated by 5-aza-CdR treatment, but they were sensitive to knockdown of H3K9 methyltransferases. Unlike the situation in embryonic stem cells, the polycomb repressive complex (PRC2) has a minor role in LTR suppression by itself and is only a player after removal of cytosine methylation in the analyzed cancer cell line. Up-regulation of LTRs and induction of “viral mimicry” is rapidly becoming of interest for predicting cancer patient response to epigenetic therapies. Understanding the mechanism for LTR suppression is of major importance in order to improve patient treatment strategies.
登录
查看更多内容
影响因子：
50.3
作者：
De Carvalho DD;Sharma S;You JS;Su SF;Taberlay PC;Kelly TK;Yang X;Liang G;Jones PA
通讯作者：
Jones PA
影响因子：
4.4
作者：
Colmegna, Ines;Garry, Robert F.
通讯作者：
Garry, Robert F.
影响因子：
14.8
作者：
Brand, Marjorie;Rampalli, Shravanti;Dilworth, F. Jeffrey
通讯作者：
Dilworth, F. Jeffrey
DOI：
10.1073/pnas.0604602103
发表时间：
2006-09-19
影响因子：
11.1
作者：
Egger, Gerda;Jeong, Shinwu;Liang, Gangning
通讯作者：
Liang, Gangning
DNMT和HDAC抑制剂诱导长时间重复序列编码的隐秘转录起始位点。
影响因子：
30.8
作者：
Brocks D;Schmidt CR;Daskalakis M;Jang HS;Shah NM;Li D;Li J;Zhang B;Hou Y;Laudato S;Lipka DB;Schott J;Bierhoff H;Assenov Y;Helf M;Ressnerova A;Islam MS;Lindroth AM;Haas S;Essers M;Imbusch CD;Brors B;Oehme I;Witt O;Lübbert M;Mallm JP;Rippe K;Will R;Weichenhan D;Stoecklin G;Gerhäuser C;Oakes CC;Wang T;Plass C
通讯作者：
Plass C