Department of Molecular Immunology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Sector 39A, Chandigarh, 160036, India.
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA.
Cell Mol Life Sci. 2022 May 21;79(6):308. doi: 10.1007/s00018-022-04323-0.
Nuclear receptors are a unique family of transcription factors that play cardinal roles in physiology and plethora of human diseases. The adopted orphan nuclear receptor Nr1d1 is a constitutive transcriptional repressor known to modulate several biological processes. In this study, we found that Nr1d1 plays a decisive role in T helper (Th)-cell polarization and transcriptionally impedes the formation of Th2 cells by directly binding to the promoter region of GATA binding protein 3 (GATA3) gene. Nr1d1 interacts with its cellular companion, the nuclear receptor corepressor and histone deacetylase 3 to form a stable repression complex on the GATA3 promoter. The presence of Nr1d1 also imparts protection against associated inflammatory responses in murine model of asthma and its ligand SR9011 eased disease severity by suppressing Th2 responses. Moreover, Chip-seq profiling uncovered Nr1d1 interactions with other gene subsets that impedes Th2-linked pathways and regulates metabolism, immunity and brain functions, therefore, providing empirical evidence regarding the genetic link between asthma and other comorbid conditions. Thus, Nr1d1 emerges as a molecular switch that could be targeted to subdue asthma.
核受体是一类独特的转录因子家族，它们在生理学和众多人类疾病中起着至关重要的作用。被采用的孤儿核受体 Nr1d1 是一种组成型转录抑制剂，已知可调节多种生物学过程。在这项研究中，我们发现 Nr1d1 在辅助性 T 细胞（Th）极化中起决定性作用，并通过直接结合 GATA 结合蛋白 3（GATA3）基因的启动子区域，转录性地阻碍 Th2 细胞的形成。Nr1d1 与细胞伴侣核受体共抑制因子和组蛋白去乙酰化酶 3 相互作用，在 GATA3 启动子上形成稳定的抑制复合物。Nr1d1 的存在也赋予了哮喘小鼠模型对相关炎症反应的保护作用，其配体 SR9011 通过抑制 Th2 反应来减轻疾病严重程度。此外，Chip-seq 分析揭示了 Nr1d1 与其他基因亚群的相互作用，这些基因亚群抑制了 Th2 相关途径，并调节代谢、免疫和大脑功能，因此为哮喘和其他合并症之间的遗传联系提供了经验证据。因此，Nr1d1 作为一种分子开关，可以被靶向以抑制哮喘。
