Transcriptional Profiling of Monocytes Deficient in Nuclear Orphan Receptors NR4A2 and NR4A3 Reveals Distinct Signalling Roles Related to Antigen Presentation and Viral Response.
Transcriptional Profiling of Monocytes Deficient in Nuclear Orphan Receptors NR4A2 and NR4A3 Reveals Distinct Signalling Roles Related to Antigen Presentation and Viral Response.
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DOI：
10.3389/fimmu.2021.676644
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发表时间：
2021
影响因子：
7.3
通讯作者：
Cummins EP
中科院分区：
文献类型：
--
作者：
Phelan DE;Shigemura M;Aldhafiri S;Mota C;Hall TJ;Sznajder JI;Murphy EP;Crean D;Cummins EP
核受体亚家族4组A （NR4A）家族是早期反应基因，其编码的蛋白质在多种组织/细胞中被激活，以响应各种应激源。NR4A家族包括NR4A1、NR4A2和NR4A3，其中NR4A2和NR4A3研究较少，特别是在免疫细胞的背景下。NR4A的表达与关节炎、动脉粥样硬化等多种疾病有关，开发以NR4A为靶点的分子作为治疗药物是目前该研究领域的热点。在这里，我们使用rna测序结合战略性生物信息学分析来研究NR4A2和NR4A3在单核细胞中的下游作用，并剖析它们共同和独特的信号作用。我们的数据显示NR4A2和NR4A3缺失在非刺激状态和LPS存在下都对转录具有强大而广泛的影响。有趣的是，许多受影响的基因在未受刺激和受刺激的状态下都存在，这揭示了nr4a在未受刺激的细胞中以前未被认识到的作用。策略聚类和生物信息学分析确定了NR4A2和NR4A3在单核细胞中的不同和共同的转录作用。生物信息学聚类分析和转录因子相互作用组分析都将NR4A2与抗原呈递和MHC基因调控相关的途径联系起来。相比之下，NR4A3与病毒反应相关的途径联系更紧密。功能研究进一步支持我们的数据分析，指出NR4A2在抗原加工调控中具有优先/选择性作用，NR4A2和NR4A3在细胞迁移方面具有明显的共同作用。综上所述，本研究为单核细胞中神秘的核受体NR4A2和NR4A3的作用提供了新的机制见解。
The nuclear receptor sub-family 4 group A (NR4A) family are early response genes that encode proteins that are activated in several tissues/cells in response to a variety of stressors. The NR4A family comprises NR4A1, NR4A2 and NR4A3 of which NR4A2 and NR4A3 are under researched and less understood, particularly in the context of immune cells. NR4A expression is associated with multiple diseases e.g. arthritis and atherosclerosis and the development of NR4A-targetting molecules as therapeutics is a current focus in this research field. Here, we use a combination of RNA-sequencing coupled with strategic bioinformatic analysis to investigate the down-stream effects of NR4A2 and NR4A3 in monocytes and dissect their common and distinct signalling roles. Our data reveals that NR4A2 and NR4A3 depletion has a robust and broad-reaching effect on transcription in both the unstimulated state and in the presence of LPS. Interestingly, many of the genes affected were present in both the unstimulated and stimulated states revealing a previously unappreciated role for the NR4As in unstimulated cells. Strategic clustering and bioinformatic analysis identified both distinct and common transcriptional roles for NR4A2 and NR4A3 in monocytes. NR4A2 notably was linked by both bioinformatic clustering analysis and transcription factor interactome analysis to pathways associated with antigen presentation and regulation of MHC genes. NR4A3 in contrast was more closely linked to pathways associated with viral response. Functional studies further support our data analysis pointing towards preferential/selective roles for NR4A2 in the regulation of antigen processing with common roles for NR4A2 and NR4A3 evident with respect to cell migration. Taken together this study provides novel mechanistic insights into the role of the enigmatic nuclear receptors NR4A2 and NR4A3 in monocytes.
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影响因子：
3.7
作者：
Lim TS;Goh JK;Mortellaro A;Lim CT;Hämmerling GJ;Ricciardi-Castagnoli P
通讯作者：
Ricciardi-Castagnoli P
影响因子：
--
作者：
Lee, Syng-Ook;Li, Xi;Safe, Stephen
通讯作者：
Safe, Stephen
影响因子：
11.4
作者：
Cheng, LEC;Chan, FKM;Winoto, A
通讯作者：
Winoto, A
影响因子：
5.5
作者：
Crean D;Murphy EP
通讯作者：
Murphy EP
影响因子：
64.5
作者：
Förster, R;Schubel, A;Lipp, M
通讯作者：
Lipp, M