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Intrinsic B cell epigenetic regulation of antibody and autoantibody responses by Sirt1

Sirt1 对抗体和自身抗体反应的内在 B 细胞表观遗传调控

基本信息

批准号：
10544531
负责人：
Paolo Casali
金额：
$ 47.44万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-14 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544531
关键词：
3&apos Untranslated Regions ATAC-seq Ablation Acetylation Address Aftercare Aging Allergens Animal Model Antibodies Antibody Response Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity B cell differentiation B-Cell Activation B-Lymphocytes Back Bacteria Biochemistry Biosensor Cell physiology Cellular biology ChIP-seq Cues DNA Methylation DNA Modification Methylases Data Deacetylation Dependence Development Diabetes Mellitus Dietary Fiber Down-Regulation Elements Epigenetic Process Gene Expression Genes Genetic Genetic Predisposition to Disease Genetic Recombination Genetic Transcription Genome Glucose Goals Grant Histone Deacetylase Histone Deacetylase Inhibitor Histone Deacetylation Histone H3 Histones Homeostasis Human Image Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Somatic Hypermutation Immunoglobulins In Vitro Internal Ribosome Entry Site Luciferases Lupus MYB gene Malignant Neoplasms Mediating Mediator Memory Memory B-Lymphocyte Metabolic MicroRNAs Modification Molecular Mouse Strains Mus Mutate NF-kappa B Patients Phase Plasma Cells Post-Translational Protein Processing Pristane Process Regulation Reporter Rest Role SIRT1 gene SLEB1 gene Signal Pathway Sirtuins Stimulus Supplementation Systemic Lupus Erythematosus Testing Therapeutic Transcription Coactivator Transcription Repressor USF1 gene Untranslated RNA Up-Regulation Virus Volatile Fatty Acids Water Work activation-induced cytidine deaminase animal imaging cell type cofactor demethylation ds-DNA epigenetic regulation experimental study gut microbiota human model humanized mouse immunoregulation in vivo inhibiting antibody innovation insight nicotinamide-beta-riboside non-histone protein novel novel therapeutics organ injury overexpression plasma cell differentiation programs promoter response sensor small molecule stem systemic autoimmunity therapeutic target tissue injury tool transcriptome sequencing

项目摘要

PROJECT SUMMARY We want to unveil novel fundamental B cell-intrinsic epigenetic mechanisms that maintain B cell homeostasis and inform B cell processes critical to the antibody response to exogenous antigens (e.g., viruses, bacteria) and self-antigens (e.g., dsDNA, RNPs in systemic lupus). As we have shown in the first cycle of this grant, epigenetic mechanisms interact with genetic programs to modulate AID (encoded by AICDA/Aicda) expression, critical for SHM/CSR. Indeed, Zn2+-dependent Class I, II and IV HDACs promote AID induction and SHM/CSR in a B cell-intrinsic fashion. AID induction is dampened by Class I, II and IV HDAC inhibitors, such as short- chain fatty acids produced by gut microbiota via processing of dietary fibers, through upregulation of select microRNAs that target AICDA/Aicda 3’UTR, leading to abrogation of antibody/autoantibody responses. Prompted by our most recent and compelling findings on Sirt1, a NAD+-dependent Class III HDAC and metabolic sensor implicated in aging, cancer and diabetes, we hypothesize that this Sirtuin dampens AID (a role opposite to that of Class I, II and IV HDACs) in a B cell-intrinsic fashion, and regulation of Sirt1 expression or activity effectively modulates SHM/CSR and antibody/autoantibody responses. As we contend, high Sirt1 levels/activity would effect homeostatic Aicda silencing in resting B cells, the first phase of a tri-phasic fluctuation of reciprocal Sirt1 and AID expression, as followed by low Sirt1 and high AID in activated B cells and back to high Sirt1 to low AID in plasma cells and memory B cells. Sirt1 would modulate AID expression through a three-prong histone and non-histone protein deacetylation. It would also enforce a B cell-intrinsic metabolic–epigenetic checkpoint of AID upregulation since Sirt1 cofactor NAD+ integrates metabolic cues. Our strengths in B cell biology, molecular SHM/CSR mechanisms and autoimmunity, as well as our cutting- edge epigenetic approaches (ChIP-Seq, methylDNA-Seq and ATAC-Seq), new tools in biochemistry (NAD+ biosensor), genetics (Cd19+/Cre-Ert2Sirt16fl/flRosa26fl-STOP-fl-tdTomato and Cd19+/Cre-Ert2Rosa26fl-STOP-fl-Sirt1-IRES-Gfp mice), imaging (AicdaCreRosa26fl-STOP-fl-luciferase reporter mice), and animal models of human antibody/autoantibody responses (humanized NSG/cKitW-41J mice) make us uniquely poised to test our hypotheses. Aim1 addresses human and mouse B cell differentiation stage-specific regulation of Sirt1 expression and NAD+ levels, and underlying mechanisms, with focus on transcription activator USF1, transcription repressor c-Myb and microRNAs targeting Sirt1 3’UTR. Aim 2 addresses B cell Sirt1 role in dampening AICDA/Aicda expression through genetics and/or compounds/metabolites, and defines underlying H3K4Ac, H3K36Ac, Dnmt1 and NF- kB deacetylation mechanisms; Aim 3 addresses the inhibition of antibody and autoantibody responses by B cell Sirt1 and Sirt1 activators, and explores Sirt1 activators as therapeutics in systemic lupus. Our highly significant and innovative experiments will provide novel mechanistic insights into B cell epigenetics and immunoregulation, and yield metabolic-epigenetic checkpoint modulators as new therapeutics in autoimmunity.!

项目总结我们想要揭示维持B细胞动态平衡的新的基本B细胞内在表观遗传机制并告知对外源性抗原(如病毒、细菌)的抗体反应至关重要的B细胞过程和自身抗原(如系统性红斑狼疮中的dsDNA、RNPs)。正如我们在这笔赠款的第一个周期中所表明的，表观遗传机制与遗传程序相互作用以调节AID(由AICDA/Aicda编码)表达，对SHM/CSR至关重要。事实上，依赖锌离子的I、II和IV类HDAC促进AID诱导和SHM/CSR 以B细胞固有的方式。辅助诱导受到I、II和IV类HDAC抑制剂的抑制，如Short- 肠道微生物通过加工膳食纤维，通过上调SELECT基因表达而产生的链脂肪酸靶向AICDA/Aicda 3‘非编码区的microRNAs，导致抗体/自身抗体反应的消除。根据我们关于Sirt1的最新和令人信服的发现，依赖NAD+的III类HDAC和代谢感受器与衰老、癌症和糖尿病有关，我们假设这种Sirtuin抑制AID(a 与I、II和IV类HDAC相反的作用)在B细胞固有的方式中，以及Sirt1表达的调节 OR活性有效地调节SHM/CSR和抗体/自身抗体反应。正如我们所争辩的，高Sirt1 水平/活动将影响静息B细胞的动态平衡Aicda沉默，这是三相B细胞的第一阶段激活的B细胞中Sirt1和AID的相互表达以及随后的低Sirt1和高AID的波动浆细胞和记忆B细胞由高Sirt1到低AID。SIRT1将调控艾滋病病毒的表达通过三管齐下的组蛋白和非组蛋白去乙酰化。它还将强制B细胞固有的自Sirt1辅因子NAD+整合代谢信号以来，艾滋病上调的代谢-表观遗传学检查点。我们在B细胞生物学、分子SHM/CSR机制和自身免疫方面的优势，以及我们的切割- 边缘表观遗传学方法(CHIP-SEQ、甲基DNA-SEQ和ATAC-SEQ)，生物化学的新工具(NAD+ 生物传感器)，遗传学(Cd19+/Cre-Ert2Sirt16fl/flRosa26fl-STOP-fl-tdTomato和Cre-Ert2Rosa26fl-Stop-fl-Sirt1-IRES-Gfp小鼠)，成像(AicdaCreRosa26fl-Stop-fl-荧光素酶报告鼠)和人类抗体/自身抗体的动物模型反应(人源化的NSG/cKitW-41J小鼠)使我们独一无二地准备检验我们的假设。AIM1地址人和小鼠B细胞分化阶段对Sirt1表达和NAD+水平的特异性调节，以及潜在的机制，重点是转录激活因子USF1，转录抑制因子c-Myb和靶向Sirt1 3‘非编码区的microRNA。目的2探讨B细胞Sirt1在抑制AICDA/Aicda表达中的作用通过遗传学和/或化合物/代谢物，并定义潜在的H3K4Ac，H3K36Ac，Dnmt1和NF- KB去乙酰化机制；目标3解决B对抗体和自身抗体反应的抑制细胞Sirt1和Sirt1激活剂，并探索Sirt1激活剂在系统性红斑狼疮治疗中的作用。我们的高度重视重大和创新的实验将提供对B细胞表观遗传学和免疫调节，并产生代谢-表观遗传检查点调节剂作为自身免疫的新疗法。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rad52 competes with Ku70/Ku86 for binding to S-region DSB ends to modulate antibody class-switch DNA recombination.

DOI：
10.1038/ncomms14244
发表时间：
2017-02-08
期刊：
Nature communications
影响因子：
16.6
作者：
Zan H;Tat C;Qiu Z;Taylor JR;Guerrero JA;Shen T;Casali P
通讯作者：
Casali P

TSPAN33 is a novel marker of activated and malignant B cells.

DOI：
10.1016/j.clim.2013.08.005
发表时间：
2013-12
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
0
作者：
Luu VP;Hevezi P;Vences-Catalan F;Maravillas-Montero JL;White CA;Casali P;Llorente L;Jakez-Ocampo J;Lima G;Vilches-Cisneros N;Flores-Gutiérrez JP;Santos-Argumedo L;Zlotnik A
通讯作者：
Zlotnik A

Epigenetics of Peripheral B-Cell Differentiation and the Antibody Response.