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The epigenetic reader BRWD1 in peripheral adaptive immunity

外周适应性免疫中的表观遗传阅读器 BRWD1

基本信息

批准号：
10541126
负责人：
Marcus Ramsay Clark
金额：
$ 48.78万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-10 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541126
关键词：
3-Dimensional ATAC-seq Affect Affinity Alleles Antibodies Antigens Applications Grants Attenuated Autoimmunity B-Cell Development B-Lymphocytes Binding Binding Sites Bone Marrow Cells ChIP-seq Characteristics Chimera organism Chromatin Chromatin Structure DNA Darkness Data Defect Development Enhancers Ephrin-A5 Epigenetic Process Failure Flow Cytometry Follicular Dendritic Cells Gene Expression Profile Gene Expression Regulation Genes Genetic Transcription Genome Heterogeneity Hi-C Histologic Human Humoral Immunities IRF4 gene IgK Immunization Immunize Immunoglobulin Class Switching In Situ Infection Knowledge Light Lymphopoiesis Malignant Neoplasms Molecular Mus Mutation Nucleosomes Patients Pattern Peripheral Phenotype Population Positioning Attribute Reader Regulation Reporting Repression Role Shapes Sorting Structure Structure of germinal center of lymph node T-Lymphocyte Testing Transcriptional Regulation WD Repeat Work adaptive immunity design differential expression fighting genome-wide hypogammaglobulinemia lymph nodes molecular modeling novel novel therapeutics programs quantitative imaging recruit response single-cell RNA sequencing three dimensional structure transcription factor vaccine efficacy

项目摘要

PROJECT SUMMARY Recently, we demonstrated that the lineage-restricted BROMO and WD40 domain containing epigenetic reader BRWD1 opens Igk and induces an epigenetic landscape that enables assembly of RAG proteins at Jk. We now report that BRWD1 has a much broader role in late B cell development. BRWD1 reshapes chromatin landscapes by closing enhancers of genes expressed early in B cell development and opening those of genes expressed in late stages. BRWD1 did not affect the expression of critical transcription factors (TFs). Rather, as demonstrated for IRF4, BRWD1 determines the sites they bind across the genome. BRWD1 differentially regulated over 7000 genes, repressing proliferative and inducing differentiation programs. Notably, BRWD1 coordinately repressed Myc and Myc target genes. Furthermore, in humans, BRWD1 mutations are associated with hypogammaglobulinemia. These data indicate that, in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B cell development. BRWD1 is first expressed in small pre-B cells. However, Brwd1 expression is higher in naïve follicular (FO) and in germinal center (GC) dark zone (DZ) cells. Analysis of genes differentially expressed in GC DZ and light zone (LZ) cells, compared to those differentially regulated by BRWD1 in small pre-B cells, predicts that BRWD1 represses the DZ program and induces the LZ program. Furthermore, differential genome-wide binding of BRWD1 in DZ and LZ cells suggests different functions in each GC subset. Immunizing Brwd1fl/fl x Aicda (AID)- Cre mice revealed that BRWD1 was required for normal antibody isotype switching and affinity maturation. Histologically, GCs were greatly reduced in both size, and number, and lacked follicular dendritic cells. Therefore, we hypothesize that BRWD1 regulates epigenetic states and enhancer landscapes critical for coordination of DZ and LZ transcriptional programs and GC function. We will test this hypothesis in the following Specific Aims: Aim 1. Determine the transcriptional regulation of normal germinal center responses. Aim 2. Determine the role of BRWD1 in adaptive immunity. Aim 3. Determine the role of BRWD1 in initiating GC responses and in maintaining FO B cell identity. !

项目总结最近，我们证明了包含表观遗传阅读器的血统受限的Bromo和WD40结构域 BRWD1打开IgK并诱导表观遗传格局，使RAG蛋白能够在JK处组装。我们现在有报道称，BRWD1在晚期B细胞发育中具有更广泛的作用。BRWD1重塑染色质景观通过关闭在B细胞发育早期表达的基因的增强子，并打开在B细胞发育早期表达的基因的增强子后期阶段。BRWD1不影响关键转录因子(TF)的表达。相反，正如所展示的那样对于IRF4，BRWD1决定它们在整个基因组中结合的位置。BRWD1差异调节超过7000 基因，抑制增殖和诱导分化程序。值得注意的是，BRWD1被协调抑制 Myc和Myc靶基因。此外，在人类中，BRWD1突变与低丙种球蛋白血症。这些数据表明，在小鼠和人类中，BRWD1都是一个主要的协调者增强可及性，与转铁蛋白网络合作，推动晚期B细胞发育。 BRWD1首先在小的Pre-B细胞中表达。而Brwd1在幼稚卵泡(FO)中的表达较高。生发中心(GC)暗区(DZ)细胞。GC、DZ和LIGHT差异表达基因的分析在小的Pre-B细胞中，与受BRWD1差异调控的细胞相比，区(LZ)细胞预测BRWD1 抑制DZ程序并诱导LZ程序。此外，差异全基因组结合 DZ和LZ细胞中的BRWD1在每个GC亚群中具有不同的功能。免疫Brwd1fl/fl x Aicda(AID)- CRE小鼠发现BRWD1是正常抗体亚型转换和亲和力成熟所必需的。组织学上，GCs的大小和数量均显著减少，并且缺乏滤泡树突状细胞。因此，我们假设BRWD1调控表观遗传状态和对DZ协调至关重要的增强子景观以及LZ转录程序和GC功能。我们将在以下具体目标中检验这一假设：目的1.确定正常生发中心反应的转录调控。目的2.确定BRWD1在获得性免疫中的作用。目的3.确定BRWD1在启动GC反应和维持FO B细胞特性中的作用。好了！