HIV-1 active and latent infections induce disparate chromatin reorganization and transcriptional regulation of mRNAs and lncRNAs in SupT1 cells.
HIV-1 active and latent infections induce disparate chromatin reorganization and transcriptional regulation of mRNAs and lncRNAs in SupT1 cells.
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作者：
HIV-1潜伏期是一个多维、动态的过程，病毒潜伏期如何建立和维持的许多方面仍未完全表征。我们已经研究了宿主细胞表观基因组和转录组微环境如何根据病毒的转录状态进行比较。使用双报告病毒，我们发现了活化和潜伏HIV-1感染的SupT1细胞在染色质重组和细胞基因表达模式上的显著差异。潜伏性HIV-1感染诱导的细胞表观基因组重组明显多于活动性感染。此外，在HIV-1感染的两种状态之间，表观基因组变化的性质也有所不同。潜伏性HIV-1感染的大多数变化是抑制性的，而活性病毒感染导致染色质可及性的总体增加。潜伏感染中被抑制的染色质重塑与参与DNA复制、DNA修复和细胞周期途径的基因下调有关，而活跃感染中开放的染色质结构导致脂质代谢、囊泡和小分子运输途径富集的基因表达增加。与细胞mrna类似，我们的综合转录组学分析也发现了长链非编码RNA （lncRNA）表观基因组和表达谱在活跃和潜伏HIV-1感染之间的显著变化。在活动性和潜伏性HIV-1感染中，与细胞通路失调相关的新型lncRNA的推测功能被确定，病毒再激活对潜伏感染细胞中lncRNA表达的影响被评估。这项研究表明，HIV-1潜伏感染比HIV-1活动性感染需要更大的细胞表观基因组和转录组的改变。HIV-1感染t淋巴细胞依赖于选择细胞转录和翻译机制进行病毒复制。这需要细胞微环境发生重大变化。我们描述并比较了活跃或潜伏感染HIV-1的T细胞中细胞染色质结构的变化以及基因表达景观。我们的研究结果表明，在hiv -1感染的T细胞中，蛋白质编码mrna和非编码lncrna的染色质可及性和表达都受到独特的调控，这取决于病毒是主动转录还是保持转录沉默、潜伏状态。HIV-1潜伏感染在细胞染色质组织中引起比活性病毒感染更强烈的变化。我们的分析还确定了这种表观基因组变化对细胞基因表达和随后的生物学途径的影响。本研究在体外SupT1细胞模型中全面表征了支持活跃和潜伏HIV-1感染的细胞表观基因组和转录组状态。
HIV-1 latency is a multi-dimensional, dynamic process, and many aspects of how the viral latency is established and maintained remain incompletely characterized. We have investigated how the host cellular epigenomic and transcriptomic microenvironments compare depending on the transcriptional state of the virus. Using a dual-reporter HIVGKO virus, we identified a significant divergence in chromatin reorganization and cellular gene expression patterns between active and latent HIV-1 infections of SupT1 cells. Latent HIV-1 infection induced significantly more cellular epigenomic restructuring than active infection. Furthermore, the nature of epigenomic changes also differed between the two states of HIV-1 infection. The majority of the changes in latent HIV-1 infection were repressive, whereas active viral infection led to an overall increase in chromatin accessibility. The repressed chromatin remodeling in latent infection was associated with the downregulation of genes involved in DNA replication, DNA repair, and cell cycle pathways, whereas the open chromatin structure in active infection led to increased expression of genes enriched for lipid metabolism, vesicle, and small molecule transport pathways. Similar to cellular mRNAs, our comprehensive transcriptomic analysis also identified a significant shift in long non-coding RNA (lncRNA) epigenomic and expression profiles between active and latent HIV-1 infections. Putative functional roles of novel lncRNAs associated with cellular pathways dysregulated in active and latent HIV-1 infections were identified, and the effects of viral reactivation on lncRNA expression in latently infected cells were evaluated. This study revealed that HIV-1 latent infection necessitates substantially greater alterations in the cellular epigenome and transcriptome than active HIV-1 infection. HIV-1 infection of T-lymphocytes depends on co-opting cellular transcriptional and translational machineries for viral replication. This requires significant changes in the cellular microenvironment. We have characterized and compared the changes in cellular chromatin structures as well as gene expression landscapes in T cells that are either actively or latently infected with HIV-1. Our results reveal that chromatin accessibility and expression of both protein-coding mRNAs and non-coding lncRNAs are uniquely regulated in HIV-1-infected T cells, depending on whether the virus is actively transcribing or remains in a transcriptionally silent, latent state. HIV-1 latent infection elicits more robust changes in the cellular chromatin organization than active viral infection. Our analysis also identifies the effects of such epigenomic changes on the cellular gene expression and subsequent biological pathways. This study comprehensively characterizes the cellular epigenomic and transcriptomic states that support active and latent HIV-1 infection in an in vitro model of SupT1 cells.
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影响因子：
6.4
作者：
Chang ST;Sova P;Peng X;Weiss J;Law GL;Palermo RE;Katze MG
通讯作者：
Katze MG
影响因子：
4.8
作者：
DeHart, Jason L.;Zimmerman, Erik S.;Planelles, Vicente
通讯作者：
Planelles, Vicente
影响因子：
6.4
作者：
Dobrowolski, Curtis;Valadkhan, Saba;Karn, Jonathan
通讯作者：
Karn, Jonathan
影响因子：
6.4
作者：
Chao, Ti-Chun;Zhang, Qiong;Rana, Tariq M.
通讯作者：
Rana, Tariq M.
DOI：
10.1073/pnas.95.15.8869
发表时间：
1998-07-21
影响因子：
11.1
作者：
Chun, TW;Engel, D;Fauci, AS
通讯作者：
Fauci, AS