Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily 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 HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of 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, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.

中文翻译：

---

DNMT和HDAC抑制剂诱导长末端重复序列中编码的隐秘转录起始位点。

主要基于候选基因方法，已经提出了几种针对DNA甲基转移酶和组蛋白脱乙酰基酶抑制剂（DNMTi和HDACi）的作用机理。然而，人们对其全基因组转录和表观基因组的后果知之甚少。通过映射全局转录起始位点（TSS）和染色质动力学，我们观察了DNMTi和HDACi处理后成千上万种治疗诱导的非注释TSS（TINAT）的隐秘转录。所得的转录本经常剪接成蛋白编码外显子，并编码截短或嵌合的ORF，翻译成具有预测的异常或免疫原性功能的产物。DNMTi处理后的TINAT转录与DNA低甲基化和经典启动子组蛋白标记的获得相吻合，而HDACi与H2AK9ac，H3K14ac和H3K23ac相关地特异性诱导了TINAT的一个子集。尽管存在这种机制上的差异，但两种抑制剂均会收敛诱导相同位点的转录，因为我们发现TINATs被编码在ERV9 / LTR12家族的单个长末端重复序列中，而在实际上所有正常细胞中都被表观遗传所抑制。