Mechanism of Transcriptional Regulation of Th2 Cell Development

Th2细胞发育的转录调控机制

• 批准号: 10716014
• 负责人: Kalung Cheung
• 金额: $ 65.7万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-09 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716014
• 关键词: Acetylation; Affect; Allergic Disease; Allergic inflammation; Asthma; Atopic Dermatitis; Binding; Bromodomain; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cells; Chemicals; Chromatin; Complex; Crohn' s disease; Cues; Development; Disease; Down-Regulation; Ensure; FOXP3 gene; Future; GATA3 gene; Gene Activation; Gene Expression; Gene Order; Genetic Transcription; Genomics; Histone H3; Human Biology; Immunomodulators; Inflammatory; Interleukin-4; Ligands; Ligase; Lysine; Mediating; Methods; Methylation; Molecular; Mus; Ovalbumin; Pathogenicity; Physiological; Polycomb; Protein Family; Proteins; Pyroglyphidae; Regulation; Regulatory T-Lymphocyte; Repression; Role; Specific qualifier value; Therapeutic; Thymus Gland; Time; Transcriptional Activation; Transcriptional Regulation; Treatment Efficacy; Treatment-related toxicity; Ubiquitination; Work; YY1 Transcription Factor; adaptive immunity; allergic airway inflammation; asthma model; base; cell type; cytokine; derepression; design; effective therapy; gene repression; genetic approach; histone acetyltransferase; human disease; immunoregulation; in vivo; inhibitor; insight; member; mouse model; neutralizing antibody; next generation; novel; novel therapeutic intervention; programs; protein degradation; response; transcription factor; transcriptomics; transdifferentiation

PROJECT SUMMARY CD4+ T helper (Th) cells of different Th1, Th2, Th17 and Treg subtypes, developed in thymus, have important functions in adaptive immunity. Their dysregulation has also been implicated in diseases such as Th2- associated inflammatory and allergic diseases including asthma, Crohn’s disease and atopic dermatitis. Th2 lineage-specific differentiation from naïve CD4+ T cells is tightly controlled by cytokines (IL-4, 5, 13) through highly ordered subtype-specific gene transcription directed by a set of transcription factors and regulators with opposing activities to promote (YY1, Gata3, Stat6) or inhibit (Foxp3) Th2 cell differentiation. However, the underlying molecular mechanism remains elusive. BRD4, a key member of the bromodomain and extra- terminal (BET) protein family, is well known for its role in gene transcriptional activation, but whether and how it functions in gene transcriptional repression in a cell-type specific manner has remained elusive. Recently, we discovered that Brd4 works with Polycomb repressive complex 2 (PRC2) to repress transcriptional expression of Th2-negative regulators Foxp3 and E3-ubiqutin ligase Fbxw7 in lineage-specific differentiation of Th2 cells from mouse primary naïve CD4+ T cells. Brd4 through its second bromodomain (BD2) binds to lysine- acetylated-EED subunit of the PRC2 complex to control target gene repression through histone H3 lysine 27 trimethylation (H3K27me3). We found that Foxp3 represses transcription of Th2-specific transcription factor Gata3, while Fbxw7 controls Gata3 protein stability via ubiquitination-mediated protein degradation, which in turn ensures Gata3-mediated transcriptional activation of Th2 cytokines including Il4, Il5 and Il13. Chemical inhibition of BRD4 BD2 induces transcriptional de-repression of Foxp3 and Fbxw7, and transcriptional down- regulation of Il4, Il5 and Il13, resulting in inhibition of Th2 cell differentiation. Our study uncovers previously unappreciated BRD4 functions in directing Th2-specific gene transcriptional repression to safeguard Th2 cell lineage differentiation. Building on our promising findings, in this study, we seek to define the mechanistic details of BRD4’s transcriptional repression function in the temporal regulation of Th2 cells, develop and use new BRD4-BD2 selective inhibitors to study the transcriptional regulation of Th2 cell differentiation, and investigate the therapeutic potential of BRD4-BD2 inhibition as new Th2 immunomodulation to block Th2- associated allergic inflammation in mouse models of asthma.

项目摘要 在胸腺中开发的不同Th1，Th2，Th17和Treg亚型的CD4+ T助手（Th）细胞具有重要 适应性免疫的功能。它们的失调也与Th2-等疾病有关 相关的炎症和过敏性疾病，包括哮喘，克罗恩病和特应性皮炎。 Th2 与幼稚的CD4+ T细胞的谱系特异性分化通过细胞因子（IL-4，5，13）紧密控制 高度有序的亚型特异性基因转录，由一组转录因子和调节剂指导 相反的活动（YY1，GATA3，STAT6）或抑制（FOXP3）TH2细胞分化。但是， 潜在的分子机制仍然难以捉摸。 BRD4，溴结构域的关键成员和额外的成员 末端（BET）蛋白质家族以其在基因转录激活中的作用而闻名 基因转录表达的功能以细胞类型的特异性方式仍然难以捉摸。最近，我们 发现BRD4与Polycomb反射复合物2（PRC2）一起使用，以复制转录表达式 Th2阴性调节剂FOXP3和E3- ubiqutin连接酶FBXW7在Th2细胞的谱系特异性分化中 来自小鼠初级幼稚的CD4+ T细胞。 BRD4通过其第二溴构域（BD2）与赖氨酸结合 PRC2复合物的乙酰化 - EED亚基通过组蛋白H3赖氨酸控制靶基因表达27 三甲基化（H3K27me3）。我们发现FOXP3再现了Th2特异性转录因子的转录 GATA3，而FBXW7通过泛素化介导的蛋白质降解控制GATA3蛋白稳定性，该蛋白质降解 转弯确保GATA3介导的Th2细胞因子在内的转录激活，包括IL4，IL5和IL13。化学 BRD4 BD2的抑制会诱导FOXP3和FBXW7的转录抑制，以及转录下降 - IL4，IL5和IL13的调节，导致抑制Th2细胞分化。我们的研究以前发现 未欣赏的BRD4在将Th2特异性基因转录表示为保护Th2细胞中起作用 谱系分化。在我们的诺言发现的基础上，在这项研究中，我们试图定义机械 BRD4在Th2细胞的临时调节中的转录表达功能的详细信息，开发和使用 新的BRD4-BD2选择性抑制剂，以研究Th2细胞分化的转录调控， 研究BRD4-BD2抑制作用作为新的Th2免疫调节以阻止Th2-的治疗潜力 哮喘小鼠模型中相关的过敏性炎症。