The role of BAF related complexes in regulatory T cell development and function

BAF 相关复合物在调节性 T 细胞发育和功能中的作用

• 批准号: 10632013
• 负责人: Diana Clare Hargreaves
• 金额: $ 79.28万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632013
• 关键词: 3-Dimensional; Affect; Area; Autoimmune; Autoimmune Diseases; Autoimmunity; Binding; Binding Sites; Biochemical; Bioinformatics; Bromodomain; CRISPR/Cas technology; Cancer Model; Cell Lineage; Cell physiology; Cells; Cellular biology; ChIP-seq; Chemicals; Chromatin; Chromatin Remodeling Factor; Complex; DNA; Development; Disease Progression; Disease model; Drug usage; Epigenetic Process; Equilibrium; FOXP3 gene; Failure; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Goals; Hi-C; Homeostasis; Human; Immune response; Immune system; Impairment; Inflammatory; Insulin-Dependent Diabetes Mellitus; Knock-out; Knockout Mice; Knowledge; Lead; Link; Lymphoproliferative Disorders; Maintenance; Malignant Neoplasms; Modeling; Multiple Sclerosis; Mus; Ontology; Outcome; Outcomes Research; Play; Proteins; Regulation; Regulatory T-Lymphocyte; Repression; Research; Research Personnel; Rheumatoid Arthritis; Role; SMARCA4 gene; Screening Result; Suppressor-Effector T-Lymphocytes; System; T-Cell Development; Testing; Transcriptional Regulation; anti-tumor immune response; conditional knockout; experimental study; genome-wide; immunopathology; improved; in vivo; inhibitor; insight; loss of function mutation; melanoma; mouse model; novel; novel therapeutics; prevent; recruit; targeted treatment; transcription factor; transcriptome sequencing; tumor; tumor immunology

PROJECT SUMMARY Regulatory T cells (Treg) play a crucial role in keeping the immune system in balance and preventing autoimmune disease. Defective Treg function leads to autoimmune diseases including rheumatoid arthritis and multiple sclerosis. On the other hand, Treg cells inside tumors can block effective anti-tumor immune responses. The development and maintenance of the Treg cell lineage are dependent on the transcription factor Foxp3, as loss of function mutations lead to severe lymphoproliferative disease in mice and humans. Thus, understanding the mechanisms that govern Foxp3 induction and stability may lead to the development of novel therapies for autoimmune disease and cancer. Dr. Zheng and colleagues recently developed a system to perform genome- wide CRISPR/Cas9 knockout screens to identify Foxp3 regulators in mouse induced and natural Tregs. The unbiased screen results not only confirmed a number of known Foxp3 regulators but also revealed many novel factors that control Foxp3 expression. Gene ontology analysis of the newly identified Foxp3 regulators revealed significant enrichment of multiple genes encoding subunits of the BAF (SWI/SNF) chromatin remodeling complexes, indicating an unknown role for this regulator in Treg development. Among the three BAF related complexes, the newly described GBAF complex promotes the expression of Foxp3, whereas the PBAF complex represses its expression. Furthermore, deletion of the bromodomain-containing protein Brd9, specific to GBAF complexes, led to reduced Foxp3 expression and compromised Treg function. Additionally, bromodomain inhibitors and chemical degraders of BRD9 act similarly to Brd9 genetic deletion to impair Foxp3 expression and Treg suppressor function. RNA-seq and ChIP-seq studies suggest that Brd9 cooperates with Foxp3 to potentiate its binding to Foxp3 target genes and regulate their expression. The overall objective of this study is to define the role of BAF related complexes in Treg function through regulation of and cooperation with Foxp3. This goal will be accomplished by elucidating the role of G/PBAF in Foxp3 induction and maintenance (Aim 1), defining the biochemical association of G/PBAF complexes with Foxp3 (Aim 2), identifying the functional role of GBAF in Foxp3-dependent transcription (Aim 3), and characterizing the functional consequences of disrupting G/PBAF subunits in Tregs in autoimmune disease and cancer models (Aim 4). The outcomes of the proposed studies are expected to fundamentally advance the understanding of epigenetic control of Foxp3 gene expression and Treg transcriptional networks. Additionally, these studies will provide key insights into the function of the newly described GBAF complex and its relationship with PBAF complexes. Finally, the outcomes of this research could provide evidence to support using drugs to target BAF related complexes for the treatment of autoimmune diseases and cancer.

项目摘要 调节性T细胞（TREG）在保持免疫系统平衡并防止免疫系统方面起着至关重要的作用 自身免疫性疾病。 Treg功能有缺陷导致自身免疫性疾病，包括类风湿关节炎和 多发性硬化症。另一方面，肿瘤中的Treg细胞可以阻止有效的抗肿瘤免疫反应。 Treg细胞谱系的开发和维护取决于转录因子FOXP3，如 功能突变的丧失导致小鼠和人类的严重淋巴增生性疾病。因此，理解 控制FOXP3诱导和稳定性的机制可能会导致开发新的疗法 自身免疫性疾病和癌症。 Zheng博士及其同事最近开发了一种执行基因组的系统 宽CRISPR/CAS9淘汰赛屏幕以识别小鼠诱导和天然Treg中的FoxP3调节剂。这 公正的屏幕结果不仅证实了许多已知的FOXP3调节器，而且还揭示了许多新颖 控制FOXP3表达的因素。新鉴定的FOXP3调节剂的基因本体分析揭示了 编码BAF（SWI/SNF）染色质重塑的多个基因的显着富集 复合物，表明该调节剂在Treg开发中的作用未知。在三个BAF中 复合物，新描述的GBAF复合物促进了FOXP3的表达，而PBAF复合物 压抑其表达。此外，含溴脱域的蛋白B​​RD9的删除，特定于GBAF 复合物，导致FOXP3表达降低和Treg功能受损。另外，溴结构域 BRD9的抑制剂和化学降解器的作用类似于BRD9遗传缺失，以损害FOXP3表达和 Treg抑制器功能。 RNA-Seq和ChIP-Seq研究表明，BRD9与Foxp3合作以增强 它与FOXP3靶基因的结合并调节其表达。这项研究的总体目的是定义 通过调节和与FOXP3的合作，BAF相关复合物在Treg功能中的作用。这个目标 将通过阐明G/PBAF在FOXP3感应和维护中的作用来完成（AIM 1），定义 G/PBAF复合物与FOXP3的生化关联（AIM 2），确定了GBAF的功能作用 FOXP3依赖性转录（AIM 3），并表征破坏G/PBAF的功能后果 自身免疫性疾病和癌症模型中Treg中的亚基（AIM 4）。拟议研究的结果 期望从根本上促进对FOXP3基因表达和的表观遗传控制和 Treg转录网络。此外，这些研究将为新的功能提供关键的见解 描述了GBAF复合物及其与PBAF复合物的关系。最后，这项研究的结果可能 提供证据以支持使用药物靶向与BAF相关的复合物治疗自身免疫的证据 疾病和癌症。

项目成果

A non-canonical BRD9-containing BAF chromatin remodeling complex regulates naive pluripotency in mouse embryonic stem cells.

• DOI: 10.1038/s41467-018-07528-9
• 发表时间: 2018-12-03
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Gatchalian J;Malik S;Ho J;Lee DS;Kelso TWR;Shokhirev MN;Dixon JR;Hargreaves DC
• 通讯作者: Hargreaves DC

Foxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity.

• DOI: 10.1038/s41467-023-42647-y
• 发表时间: 2023-11-06
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Liu, Zhi;Lee, Dong-Sung;Liang, Yuqiong;Zheng, Ye;Dixon, Jesse R.
• 通讯作者: Dixon, Jesse R.

Old macrophages lose their (circadian) rhythm.

• DOI: 10.1016/j.it.2022.02.005
• 发表时间: 2022-04
• 期刊: TRENDS IN IMMUNOLOGY
• 影响因子: 16.8
• 作者: McRae, Helen M. M.;Hargreaves, Diana C. C.
• 通讯作者: Hargreaves, Diana C. C.

Chromatin openness requires continuous SWI/SNF activity.

• DOI: 10.1038/s41588-021-00781-7
• 发表时间: 2021-03
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Hargreaves DC

Glucocorticoid signaling and regulatory T cells cooperate to maintain the hair-follicle stem-cell niche.

• DOI: 10.1038/s41590-022-01244-9
• 发表时间: 2022-07
• 期刊: NATURE IMMUNOLOGY
• 影响因子: 30.5
• 作者: Liu, Zhi;Hu, Xianting;Liang, Yuqiong;Yu, Jingting;Li, Huabin;Shokhirev, Maxim N.;Zheng, Ye
• 通讯作者: Zheng, Ye