Tracing functional (epi)genomic imprints and their evolutionary origins in human defense antiviral cellular response (ChIP-Seq II)

An integral part of human cellular homeostasis substantially relies on defense transcriptional responses tailored to fight microbial pathogens, including Viruses. However, a definitive anatomy of the “virus-responsive” fates of the non-coding genome was largely elusive. Here, we exhaustively assayed the human transcriptome and epigenome under naïve and antiviral cellular states and defined remarkable reprogramming to mark the exchange of cellular fates, involving previously unspecified, unsupervised, or overlooked non-coding entities endowed with thousands of novel virus-responsive enhancers, Super-enhancers (SEs), and Repetitive DNA enhancers. These functional determinants demonstrate superior chromatin architecture, stimulus-specificity, and transcriptional fitness, and neighbor, reside proximal, or entirely coincide with hundreds of the virus-stimulated genes, while a multitude of those is bound by the master antimicrobial TFs, IRF3 or/and NFκB, upon cell infection. A plethora of these DNA elements is traced within the repetitive fate of the human genome including Simple Tandem Repeats (STRs), Dispersed Repeats (DRs) such as retrotransposons and DNA transposons, and chimeras of those, enriched in HCTFBSs recognized by IRF3 or/and NFκB and exhibits pervasive imprints in the genomes of evolutionary recent, old and ancient species, including viruses. These findings emphasize the role of the architectural and functional compartmentalization of the human epigenome in naïve and infected cells on the perplexing natural conflicts and mechanistic dependencies that impose the frontage of defense gene expression in humans. ChIP-Seq

人类细胞稳态的核心组成部分在很大程度上依赖于为抵御包括病毒在内的微生物病原体而量身定制的防御性转录应答。然而，非编码基因组的"病毒应答"命运的完整图谱在很大程度上仍未被阐明。本研究对初始（未受刺激）与抗病毒细胞状态下的人类转录组与表观基因组进行了全面检测，鉴定出显著的重编程事件以标记细胞命运的转换，其中涉及此前未被明确标注、未被注释或此前被忽视的非编码元件，这些元件携带有数千个新型病毒应答增强子、超级增强子（Super-enhancers, SEs）以及重复DNA增强子。这些功能性调控元件展现出优异的染色质结构特征、刺激特异性与转录适配性，且与数百个病毒刺激应答基因相邻、邻近或完全重合；同时，其中大量元件在细胞感染过程中会被主抗菌转录因子干扰素调节因子3（IRF3）或/和核因子κB（NFκB）结合。这类DNA元件中有大量分布于人类基因组的重复序列组分中，包括简单串联重复序列（Simple Tandem Repeats, STRs）、逆转录转座子与DNA转座子等散在重复序列（Dispersed Repeats, DRs）以及上述元件的嵌合序列；这些元件富含IRF3或/和NFκB识别的转录因子结合位点，并在包括病毒在内的近缘、古老与远古物种的基因组中留下了广泛的印记。这些研究结果凸显了初始与感染状态下人类表观基因组的结构与功能区室化，在介导人类防御基因表达的复杂自然冲突与分子机制依赖性中的关键作用。染色质免疫沉淀测序（ChIP-Seq）