DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats.
DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats.
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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。
DOI：
10.1038/ng.3889
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发表时间：
2017-07
期刊：
影响因子：
30.8
通讯作者：
Plass C
中科院分区：
文献类型：
--
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
DNA甲基转移酶和组蛋白脱乙酰酶抑制剂(DNMTi和HDACi)的几种作用机制已被提出；主要基于候选基因方法。然而，人们对它们在全基因组范围内的转录和表观基因组学后果知之甚少。通过绘制全球转录起始点(TSS)和染色质动力学图，我们观察到DNMTi和/或HDACi处理后数千个处理诱导的非注释TSS(TINATs)的隐蔽转录。由此产生的转录本经常拼接到蛋白质编码外显子，并编码截短或嵌合的开放阅读框，翻译成具有预测的异常或免疫原性功能的产物。在经典的启动子组蛋白标记中，DNMTi后的TINAT转录与DNA低甲基化和获得一致，而HDACi特异性地诱导了与H2AK9ac、H3K14ac和H3K23ac相关的TINAT亚群。尽管存在这种机制上的差异，但这两种抑制剂都一致地从相同的位置诱导转录，因为我们发现TINATs编码在LTR12家族的孤立长端重复序列中，在几乎所有正常细胞中都受到表观遗传抑制。与基因突变相比，表观遗传变化具有潜在的可逆性，这使它们成为癌症治疗的一个有吸引力的靶点。针对DNA甲基转移酶(DNMTi)和组蛋白脱乙酰基酶(HDACi)的抑制剂被用于治疗几种血液系统恶性肿瘤。然而，尽管它们已经在临床上应用了几年，但对其作用模式仍然缺乏了解。先前两项关于癌细胞中DNMTi的研究报道了源自代谢性内源性逆转录病毒(ERV)的双链RNA(DsRNA)分子上调，随后干扰素反应和病毒防御基因的诱导。然而，目前尚不清楚其他类别的表观遗传药物如何整合到这些发现中，以及是否存在候选基因方法可能遗漏的额外影响。在这里，我们通过使用全基因组图谱技术(补充图1和补充表1)全球定位了DNMTi和HDACi诱导的转录和表观基因组变化，并表明绝大多数对表观遗传调节做出转录反应的TS是隐蔽的，目前未加注释的TS编码在孤立的长末端重复序列(LTRs)中。
Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi); mainly based on candidate gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and/or HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric open reading frames translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi coincided with DNA hypomethylation and gain in classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites since we found TINATs to be encoded in solitary long-terminal repeats of the LTR12 family, epigenetically repressed in virtually all normal cells. In contrast to genetic mutations, epigenetic changes are potentially reversible, which is deeming them an attractive target for cancer treatment. Inhibitors directed against DNA methyltransferases (DNMTi) and histone deacetylases (HDACi) are used for the treatment of several haematopoietic malignancies. However, despite their clinical use for several years, there is still a lack of knowledge regarding the mode of action. Two previous studies on DNMTi in cancer cell lines reported the up-regulation of double stranded RNA (dsRNA) molecules originating from codogenic endogenous retroviruses (ERV) followed by an interferon response and the induction of viral defense genes. However, it remains unclear how other classes of epigenetic drugs integrate into these findings and whether there are additional effects, potentially missed by candidate gene approaches. Here, we globally mapped DNMTi and HDACi-induced transcriptomic and epigenomic changes by using whole-genome profiling technologies (Supplementary Fig. 1 and Supplementary Table 1) and show that the vast majority of TSSs that transcriptionally responded towards epigenetic modulation were cryptic, currently non-annotated TSSs encoded in solitary long-terminal repeats (LTRs).
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影响因子：
11.1
作者：
Bhuvanagiri M;Lewis J;Putzker K;Becker JP;Leicht S;Krijgsveld J;Batra R;Turnwald B;Jovanovic B;Hauer C;Sieber J;Hentze MW;Kulozik AE
通讯作者：
Kulozik AE
影响因子：
14.9
作者：
Almeida LG;Sakabe NJ;deOliveira AR;Silva MC;Mundstein AS;Cohen T;Chen YT;Chua R;Gurung S;Gnjatic S;Jungbluth AA;Caballero OL;Bairoch A;Kiesler E;White SL;Simpson AJ;Old LJ;Camargo AA;Vasconcelos AT
通讯作者：
Vasconcelos AT
影响因子：
14.9
作者：
Grillo G;Turi A;Licciulli F;Mignone F;Liuni S;Banfi S;Gennarino VA;Horner DS;Pavesi G;Picardi E;Pesole G
通讯作者：
Pesole G
影响因子：
7
作者：
Hashimoto K;Suzuki AM;Dos Santos A;Desterke C;Collino A;Ghisletti S;Braun E;Bonetti A;Fort A;Qin XY;Radaelli E;Kaczkowski B;Forrest AR;Kojima S;Samuel D;Natoli G;Buendia MA;Faivre J;Carninci P
通讯作者：
Carninci P
影响因子：
30.8
作者：
Cameron, EE;Bachman, KE;Baylin, SB
通讯作者：
Baylin, SB