Mechanism of Transcriptional Regulation of Th2 Cell Development

Th2细胞发育的转录调控机制

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要胸腺中发育的不同 Th1、Th2、Th17 和 Treg 亚型的 CD4+ T 辅助 (Th) 细胞具有重要作用它们的失调也与 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。幼稚 CD4+ T 细胞的谱系特异性分化受到细胞因子 (IL-4, 5, 13) 的严格控制由一组转录因子和调节因子指导的高度有序的亚型特异性基因转录促进（YY1、Gata3、Stat6）或抑制（Foxp3）Th2 细胞分化的相反活性。潜在的分子机制仍然难以捉摸，BRD4 是溴结构域和额外结构域的关键成员。末端（BET）蛋白家族因其在基因转录激活中的作用而闻名，但它是否以及如何发挥作用最近，我们仍不清楚以细胞类型特异性方式进行基因转录抑制的功能。发现 Brd4 与 Polycomb 抑制复合物 2 (PRC2) 一起抑制转录表达 Th2 阴性调节因子 Foxp3 和 E3-泛素连接酶 Fbxw7 在 Th2 细胞谱系特异性分化中的作用来自小鼠原代幼稚 CD4+ T 细胞的 Brd4 通过其第二溴结构域 (BD2) 与赖氨酸结合。 PRC2 复合体的乙酰化 EED 亚基通过组蛋白 H3 赖氨酸 27 控制靶基因抑制我们发现 Foxp3 抑制 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 蛋白质稳定性，这在转确保 Gata3 介导的 Th2 细胞因子（包括 Il4、Il5 和 Il13）的转录激活。抑制 BRD4 BD2 会诱导 Foxp3 和 Fbxw7 的转录去抑制，以及转录下调我们之前的研究发现，Il4、Il5 和 Il13 的调节会导致 Th2 细胞分化的抑制。未被重视的 BRD4 在指导 Th2 特异性基因转录抑制以保护 Th2 细胞方面的功能基于我们有希望的发现，在这项研究中，我们试图定义其机制。 BRD4 在 Th2 细胞时间调节中的转录抑制功能的详细信息、开发和使用新的 BRD4-BD2 选择性抑制剂用于研究 Th2 细胞分化的转录调控，以及研究 BRD4-BD2 抑制作为新的 Th2 免疫调节剂阻断 Th2- 的治疗潜力哮喘小鼠模型中相关的过敏性炎症。