Transcriptome-Wide Analysis Reveals Modulation of Human Macrophage Inflammatory Phenotype Through Alternative Splicing.
Transcriptome-Wide Analysis Reveals Modulation of Human Macrophage Inflammatory Phenotype Through Alternative Splicing.
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DOI：
10.1161/atvbaha.116.307573
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Reilly MP
中科院分区：
文献类型：
--
作者：
Lin J;Hu Y;Nunez S;Foulkes AS;Cieply B;Xue C;Gerelus M;Li W;Zhang H;Rader DJ;Musunuru K;Li M;Reilly MP
人类巨噬细胞可以在炎性M1和修复性M2谱上改变表型，以应对环境挑战，但促进炎症和心脏代谢疾病相关M1表型的机制仍不完全清楚。选择性剪接（AS）正在成为细胞功能的重要调节因子，但其在巨噬细胞激活中的作用在很大程度上是未知的。我们研究了在心脏代谢疾病背景下，AS在M1激活中发生的程度，并验证了用于研究人类巨噬细胞相关AS事件的功能基因组细胞模型。通过对静息、M1和M2原代人单核细胞源性巨噬细胞的深度rna测序，我们发现3860个M1激活差异表达基因，并检测到233个M1诱导的AS事件；大多数AS事件是细胞和m1特异性的，富集与巨噬细胞炎症相关的途径。利用10个心脏代谢性状的遗传变异数据，我们在M1激活中发现了21个选择性剪接基因的基因组位点内的28个性状相关变异，以及7个差异表达的调节剪接因子中的15个变异。在原代人巨噬细胞中，敲低一种这样的剪接因子CELF1导致对M1刺激的炎症反应增加，表明CELF1可能调节M1表型。最后，我们证明了诱导多能干细胞衍生的巨噬细胞系统概括了m1相关的AS事件，并提供了高保真的巨噬细胞AS模型。AS以细胞特异性和刺激特异性的方式在巨噬细胞表型中起作用。具有性状相关变异的剪接基因和剪接因子可能揭示心脏代谢疾病的新途径和靶点。
Human macrophages can shift phenotype across the inflammatory M1 and reparative M2 spectrum in response to environmental challenges, but the mechanisms promoting inflammatory and cardiometabolic disease-associated M1 phenotypes remain incompletely understood. Alternative splicing (AS) is emerging as an important regulator of cellular function, yet its role in macrophage activation is largely unknown. We investigated the extent to which AS occurs in M1 activation within the cardiometabolic disease context and validated a functional-genomic cell model for studying human macrophage-related AS events. From deep RNA-seq of resting, M1, and M2 primary human monocyte derived macrophages, we found 3860 differentially expressed genes in M1 activation and detected 233 M1-induced AS events; the majority of AS events were cell- and M1-specific with enrichment for pathways relevant to macrophage inflammation. Using genetic variant data for 10 cardiometabolic traits, we identified in M1 activation 28 trait-associated variants within the genomic loci of 21 alternatively spliced genes and 15 variants within seven differentially expressed regulatory splicing factors. Knockdown of one such splicing factor, CELF1, in primary human macrophages led to increased inflammatory response to M1 stimulation, demonstrating CELF1's potential modulation of the M1 phenotype. Finally, we demonstrated that an induced pluripotent stem cell derived macrophage system recapitulates M1-associated AS events and provides a high-fidelity macrophage AS model. AS plays a role in defining macrophage phenotype in a cell- and stimulus-specific fashion. Alternatively spliced genes and splicing factors with trait-associated variants may reveal novel pathways and targets in cardiometabolic diseases.
影响因子：
16
作者：
Carstens, Russ P.
通讯作者：
Carstens, Russ P.