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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：
10335163
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335163
关键词：
3&apos Untranslated Regions ATAC-seq 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 Activation 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 IgG autoantibodies Image Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunoglobulins In Vitro Inbred MRL lpr Mice Internal Ribosome Entry Site Luciferases Lupus MYB gene Malignant Neoplasms Mediating Mediator of activation protein 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 Supplementation Testing Therapeutic Transcription Coactivator Transcription Repressor USF1 gene Untranslated RNA Up-Regulation Virus Volatile Fatty Acids Water 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 innovation insight nicotinamide-beta-riboside non-histone protein novel novel therapeutics organ injury overexpression 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