Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Cell Rep. 2024 Mar 26;43(3):113888. doi: 10.1016/j.celrep.2024.113888. Epub 2024 Feb 27.
Higher-order genome structure influences the transcriptional regulation of cellular genes through the juxtaposition of regulatory elements, such as enhancers, close to promoters of target genes. While enhancer activation has emerged as an important facet of Kaposi sarcoma-associated herpesvirus (KSHV) biology, the mechanisms controlling enhancer-target gene expression remain obscure. Here, we discover that the KSHV genome tethering protein latency-associated nuclear antigen (LANA) potentiates enhancer-target gene expression in primary effusion lymphoma (PEL), a highly aggressive B cell lymphoma causally associated with KSHV. Genome-wide analyses demonstrate increased levels of enhancer RNA transcription as well as activating chromatin marks at LANA-bound enhancers. 3D genome conformation analyses identified genes critical for latency and tumorigenesis as targets of LANA-occupied enhancers, and LANA depletion results in their downregulation. These findings reveal a mechanism in enhancer-gene coordination and describe a role through which the main KSHV tethering protein regulates essential gene expression in PEL.
高级基因组结构通过将调控元件（如增强子）与靶基因的启动子紧密相邻，影响细胞基因的转录调控。虽然增强子的激活已成为卡波西肉瘤相关疱疹病毒（KSHV）生物学的一个重要方面，但控制增强子-靶基因表达的机制仍不清楚。在这里，我们发现 KSHV 基因组锚定蛋白潜伏相关核抗原（LANA）增强了原发性渗出淋巴瘤（PEL）中的增强子-靶基因表达，PEL 是一种与 KSHV 因果相关的高度侵袭性 B 细胞淋巴瘤。全基因组分析表明，在 LANA 结合的增强子处，增强子 RNA 转录和激活染色质标记的水平增加。三维基因组构象分析确定了作为 LANA 占据的增强子靶点的关键基因，而 LANA 的耗竭导致其下调。这些发现揭示了增强子-基因协调的一种机制，并描述了主要的 KSHV 锚定蛋白通过该机制在 PEL 中调节关键基因表达的作用。
