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Vorinostat-induced acetylation of RUNX3 reshapes transcriptional profile through long-range enhancer-promoter interactions in natural killer cells

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Natural killer (NK) cells are an essential part of the innate immunesystem that helps control infections and tumors. Recentstudies have shown that Vorinostat, a histone deacetylase (HDAC)inhibitor, can cause significant changes in gene expression andsignaling pathways in NK cells. Since gene expression in eukaryoticcells is closely linked to the complex three-dimensional(3D) chromatin architecture, an integrative analysis of the transcriptome,histone profiling, chromatin accessibility, and 3Dgenome organization is needed to gain a more comprehensiveunderstanding of how Vorinostat impacts transcription regulationof NK cells from a chromatin-based perspective. The resultsdemonstrate that Vorinostat treatment reprograms the enhancerlandscapes of the human NK-92 NK cell line while overall 3Dgenome organization remains largely stable. Moreover, we identifiedthat the Vorinostat-induced RUNX3 acetylation is linkedto the increased enhancer activity, leading to elevated expressionof immune response-related genes via long-range enhancerpromoterchromatin interactions. In summary, these findingshave important implications in the development of new therapiesfor cancer and immune-related diseases by shedding lighton the mechanisms underlying Vorinostat’s impact on transcriptionalregulation in NK cells within the context of 3D enhancernetwork.

Abstract

Natural killer (NK) cells are an essential part of the innate immunesystem that helps control infections and tumors. Recentstudies have shown that Vorinostat, a histone deacetylase (HDAC)inhibitor, can cause significant changes in gene expression andsignaling pathways in NK cells. Since gene expression in eukaryoticcells is closely linked to the complex three-dimensional(3D) chromatin architecture, an integrative analysis of the transcriptome,histone profiling, chromatin accessibility, and 3Dgenome organization is needed to gain a more comprehensiveunderstanding of how Vorinostat impacts transcription regulationof NK cells from a chromatin-based perspective. The resultsdemonstrate that Vorinostat treatment reprograms the enhancerlandscapes of the human NK-92 NK cell line while overall 3Dgenome organization remains largely stable. Moreover, we identifiedthat the Vorinostat-induced RUNX3 acetylation is linkedto the increased enhancer activity, leading to elevated expressionof immune response-related genes via long-range enhancerpromoterchromatin interactions. In summary, these findingshave important implications in the development of new therapiesfor cancer and immune-related diseases by shedding lighton the mechanisms underlying Vorinostat’s impact on transcriptionalregulation in NK cells within the context of 3D enhancernetwork.

참고문헌 (40)

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