BRWD1 in adaptive humoral immunity
BRWD1 in adaptive humoral immunity
批准号:
9413989
负责人:
Marcus Ramsay Clark
金额:
$20.25万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-01-18 至 2018-12-31
关键词:
ATAC-seqAffinityAllelesAntibodiesAntibody AffinityAntigensApplications GrantsAreaB-Cell DevelopmentB-Lymphocyte SubsetsB-LymphocytesBCL1 OncogeneBinding SitesCXCR4 geneCell Cycle ArrestCellsChromatinCompetenceDataDevelopmentEZH2 geneEnhancersEnsureEnvironmentEphrin-A5Epigenetic ProcessFollicular Dendritic CellsGenesGeneticGenetic RecombinationGenetic TranscriptionHistonesHumoral ImmunitiesIRF4 geneImmunizeImmunoglobulin Somatic HypermutationImmunologicsInfectionLightLymphoidMaintenanceMediatingMetabolicModelingMusOrganPathway interactionsPeripheralPhenotypePlasma CellsPopulationProliferatingReaderReportingReticular CellRoleSignal TransductionStructureStructure of germinal center of lymph nodeT-LymphocyteTestingTranscription Repressor/CorepressorWD Repeatadaptive immunityantigen-specific T cellsbasedifferential expressionepigenetic regulationmigrationnovelplasma cell differentiationprogramspromoterresponsesegregationsupport networktranscription factortranscriptome sequencing
中文摘要
项目摘要
最近,我们证明了谱系限制的BROMO和WD 40结构域包含表观遗传
阅读器BRWD 1打开IGκ并使RAG蛋白能够在Jκ处组装。我们现在报告BRWD 1有一个
在晚期B细胞发育中发挥更广泛的作用。在距离结合位点最多5 mb处,BRWD 1
通过关闭在B细胞发育早期表达的基因的增强子来重塑染色质景观,
打开那些在晚期表达的基因。在BRWD 1缺失的情况下,超过7000个基因发生了异常。
表达。虽然这些基因中的许多在早期发育阶段正常表达,但许多在早期发育阶段表达。
也是Germinal Center(GC)转录程序的一部分。BRWD 1首先在小的前B细胞中表达。
然而,Brwd 1表达在幼稚卵泡(FO)中高得多,在第12天的GC B细胞中最高。鉴于
区(LZ)细胞中,BRWD 1在Myc-细胞中表达,这是一种被BRWD 1抑制的转录因子。最后,
分析GC暗区(DZ)和LZ中差异表达的基因,与那些差异表达的基因相比,
在小的前B细胞中由BRWD 1调节,预测BRWD 1抑制DZ程序并诱导细胞凋亡。
LZ程序。这些数据表明,分离增殖和IGκ的遗传程序之间存在相似性。
发育中的重组和GC中将增殖与选择分离的那些。基于这些
研究结果,我们假设BRWD 1是维持FO细胞身份所必需的。此外,我们假设
通过抑制DZ和诱导LZ遗传程序,BRWD 1对GC依赖性体液免疫至关重要。
免疫力这些假设将在以下具体目标中进行检验:
目的1:获得Brwd 1的条件等位基因。
目标二。确定BRWD 1在维持滤泡B细胞特性中的作用。
目标3。确定BRWD 1在获得性免疫中的作用。
英文摘要
PROJECT SUMMARY
Recently, we demonstrated that the lineage-restricted BROMO and WD40 domain containing epigenetic
reader BRWD1 opens Igκ and enables assembly of RAG proteins at Jκ. We now report that BRWD1 has a
much broader role in late B cell development. At distances of up to 5 mb from sites of binding, BRWD1
reshaped chromatin landscape by closing enhancers of genes expressed early in B cell development and
opening those of genes expressed in late stages. In the absence of BRWD1, over 7000 genes were aberrantly
expressed. While many of these genes were normally expressed in earlier developmental stages, many were
also part of the germinal center (GC) transcription program. BRWD1 is first expressed in small pre-B cells.
However, Brwd1 expression was much higher in naïve follicular (FO) and highest in day 12 GC B cells. In light
zone (LZ) cells, BRWD1 is expressed in Myc- cells, a transcription factor repressed by BRWD1. Finally,
analysis of genes differentially expressed in GC dark zone (DZ) and LZ, compared to those differentially
regulated by BRWD1 in small pre-B cells, predicted that BRWD1 represses the DZ program and induces the
LZ program. These data suggest similarities between genetic programs that separate proliferation and Igκ
recombination in development and those that segregate proliferation from selection in GCs. Based on these
findings, we hypothesize that BRWD1 is required for maintaining FO cell identity. Furthermore, we hypothesize
that, by repressing DZ and inducing LZ genetic programs, BRWD1 is critical for GC-dependent humoral
immunity. These hypotheses will be tested in the following Specific Aims:
Aim 1: Derive a conditional allele of Brwd1.
Aim 2. Determine role of BRWD1 in maintaining follicular B cell identity.
Aim 3. Determine the role of BRWD1 in adaptive immunity.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Comprehensive characterization of immune signaling networks in single-cells by joint quantification of proteins, protein complexes and mRNA
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批准号:10636695
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项目类别:
-
资助金额:$67.31万
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财政年份:2023
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负责人:Marcus Ramsay Clark
-
依托单位:
Medical Scientist National Research Service Award
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批准号:10869820
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项目类别:
-
资助金额:$17.42万
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财政年份:2023
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负责人:Marcus Ramsay Clark
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依托单位:
Medical Scientist National Research Service Award
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批准号:10703834
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项目类别:
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资助金额:$127.72万
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财政年份:2023
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负责人:Marcus Ramsay Clark
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依托单位:
Role of CXCR4 in immunoglobulin light chain recombination
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批准号:10569055
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项目类别:
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资助金额:$57.96万
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财政年份:2021
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负责人:Marcus Ramsay Clark
-
依托单位:
Role of CXCR4 in immunoglobulin light chain recombination
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批准号:10117864
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项目类别:
-
资助金额:$57.96万
-
财政年份:2021
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负责人:Marcus Ramsay Clark
-
依托单位:
Role of CXCR4 in immunoglobulin light chain recombination
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批准号:10368138
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项目类别:
-
资助金额:$57.96万
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财政年份:2021
-
负责人:Marcus Ramsay Clark
-
依托单位:
The epigenetic reader BRWD1 in peripheral adaptive immunity
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批准号:10541126
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项目类别:
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资助金额:$48.78万
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财政年份:2019
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负责人:Marcus Ramsay Clark
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依托单位:
The epigenetic reader BRWD1 in peripheral adaptive immunity
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批准号:10077826
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项目类别:
-
资助金额:$48.78万
-
财政年份:2019
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负责人:Marcus Ramsay Clark
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依托单位:
The epigenetic reader BRWD1 in peripheral adaptive immunity
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批准号:10321252
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项目类别:
-
资助金额:$48.78万
-
财政年份:2019
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负责人:Marcus Ramsay Clark
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依托单位:
BRWD1 in adaptive humoral immunity
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批准号:9307294
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项目类别:
-
资助金额:$24.19万
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财政年份:2017
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负责人:Marcus Ramsay Clark
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依托单位:
Regulation of Ig-kappa recombination during B lymphopoiesis
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批准号:9257272
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项目类别:
-
资助金额:$46.19万
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财政年份:2015
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负责人:Marcus Ramsay Clark
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依托单位:
Regulation of Ig-kappa recombination during B lymphopoiesis
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批准号:9474100
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项目类别:
-
资助金额:$46.19万
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财政年份:2015
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负责人:Marcus Ramsay Clark
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依托单位:
In situ tolerance in autoimmunity
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批准号:8732778
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项目类别:
-
资助金额:$7.9万
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财政年份:2014
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负责人:Marcus Ramsay Clark
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依托单位:
In vivo functions of Ig-beta ubiquitinylation
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批准号:8976272
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项目类别:
-
资助金额:$29.6万
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财政年份:2012
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负责人:Marcus Ramsay Clark
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依托单位:
In vivo functions of Ig-beta ubiquitinylation
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批准号:8595320
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项目类别:
-
资助金额:$29.6万
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财政年份:2012
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负责人:Marcus Ramsay Clark
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依托单位:
In vivo functions of Ig-beta ubiquitinylation
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批准号:8436646
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项目类别:
-
资助金额:$29.6万
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财政年份:2012
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负责人:Marcus Ramsay Clark
-
依托单位:
In vivo functions of Ig-beta ubiquitinylation
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批准号:8824783
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项目类别:
-
资助金额:$2.96万
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财政年份:2012
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负责人:Marcus Ramsay Clark
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依托单位:
Regulation of cyclin D3 in B lymphocyte development
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批准号:7983829
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项目类别:
-
资助金额:$31.65万
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财政年份:2010
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负责人:Marcus Ramsay Clark
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依托单位:
Regulation of cyclin D3 in B lymphocyte development
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批准号:8134331
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项目类别:
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资助金额:$29.94万
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财政年份:2010
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负责人:Marcus Ramsay Clark
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依托单位:
Regulation of cyclin D3 in B lymphocyte development
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批准号:8516370
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项目类别:
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资助金额:$28.89万
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财政年份:2010
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负责人:Marcus Ramsay Clark
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依托单位:
海外基金