Differentiation of memory B cells requires EZH2 and epigenetic remodeling

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

↗ Live URL (may be dead)

Document text

Principal Investigator: Keenan  Wiggins
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $27,093
Funding agency: National Institute of Allergy and Infectious Diseases

Project Summary:
It is important for an organism to develop a strong defense to repel an infection, which means
the organism must fine tune its immune system to provide efficient clearance of the pathogen.
Reponses to these different pathogens can be further divided to long lasting protection and
short-lived protection by B cells 1. In the context of B cell activation, these responses proceed in
the lymphatic system in extrafollicular space with the development of Germinal Centers (GC) 5.
The use of epigenetics allows us to understand what cellular signals contributes to cellular
differentiation after activation and what changes different pathogens create in these responses
36-39. Mouse models are an invaluable resource for studying the immune system. This study
aims to define the histone modifications in genes involved in the Memory B Cell (MBC)
transcription factor network. We want to know how MBCs differentiate and what differences are
there between GC derived and GC-independent MBCs. Some infections are cleared before
GCs are made while other infections need the advance fine tenement of B cells for the infection
to be cleared 14-16. We will study the phenotypes of MBCs and what effect H3K27 histone
modification has on MBC development and function. It has been shown for example that
challenging B cells with LPS (type-1 TI antigen) and EZH2 (the protein involved in placing
H3K27me3 marks) leads to increased antibody secreting cells 7. We know that MBCs are
epigenetically primed at genes involved in B cell activation, signal transduction, survival and
migration 28. We aim to uncover what factors support the priming necessary for B cell
differentiation in MBCs. This application seeks to test the hypothesis that GC and GC-
independent MBCs are a distinct lineage that requires specific molecular signals and
epigenetic remodeling. The Specific Aims of this project are: 1: Phenotype MBCs in an PR8
influenza response and 2: Define H3K27me3 role in the development of MBC populations. In
Aim 1, we will determine the molecular landscape of MBCs. In Aim 2, we will establish
H3K27me3 role in the formation, longevity, and reactivation of MBCs.

Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Adaptive Immune System><Address><Antibody-Secreting Cells><Antigens><Assay><B blood cells><B cell><B cell depletion therapy><B cell differentiation><B cell directed therapy><B cell lymphoma 6><B cell targeted therapy><B cell therapies><B cell therapy><B cells><B lymphocyte differentiation><B-Cell Activation><B-Cell CLL/Lymphoma-6 Gene><B-Cell Development><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><B7-1><BACH2><BACH2 gene><BB1><BCL5><BCL6><BCL6 gene><BTB and CNC Homology 2><Basal Transcription Factor><Basal transcription factor genes><Basic Leucine Zipper Transcription Factor 2><Binding><Bioassay><Biological Assay><CCR6><CCR6 gene><CD183><CD28LG><CD28LG1><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD44><CD44 gene><CD80><CD80 gene><CKR-L2><CKRL3><CMKAR3><COVID-19 virus><COVID19 virus><CXCR3><CXCR3 gene><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Cycle Progression><Cell Differentiation><Cell Differentiation process><Cell Interaction><Cell Isolation><Cell Locomotion><Cell Migration><Cell Movement><Cell Reprogramming><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell Survival><Cell Viability><Cell-to-Cell Interaction><Cells><Cellular Migration><Cellular Motility><Chemokine (C-X-C Motif) Receptor 3><Chemokine Receptor-Like 3><Chromatin><CoV-2><CoV2><Complex><Cys-His2 Zinc Finger Transcription Factor Gene><DNA Methylation><DNA Sequence><Development><Enhancers><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Functional RNA><G Protein-Coupled Receptor 29><G Protein-Coupled Receptor 9><GPR29><GPR9><GPRCY4><Gene Down-Regulation><Gene Expression><Gene Modified><Gene Transcription><GeneHomolog><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Germinal Center><Grippe><Histones><Homolog><Homologous Gene><Homologue><Humoral Immunities><IP10><IP10 Receptor><IP10-Mig receptor><IP10-R><Immune system><Immunoglobulin-Secreting Cells><Infection><Influenza><Influenza Virus><Intracellular Communication and Signaling><Knock-out><Knockout><LAB7><LAZ-3 Gene><LAZ3><Learning><Length of Life><Link><Longevity><Lymph Node Reticuloendothelial System><Lymph System><Lymph node proper><Lymphatic Network><Lymphatic System><Lymphatic System Reticuloendothelial System><Lymphatic nodes><MDU3><Maps><Mature B-Cell><Mature B-Lymphocyte><Mediating><Memory B Cell><Memory B-Lymphocyte><Mice><Mice Mammals><Mig Receptor><Mig-R><MigR><Modification><Molecular><Molecular Interaction><Murine><Mus><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleosomes><Organism><Pathway interactions><Pgp1><Phenotype><Play><Polycomb><Population><Process><Proteins><RNA Expression><Receptor Protein><Regulation><Research><Research Resources><Resources><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><STRL22><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Severities><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Spleen><Spleen Reticuloendothelial System><Structure of germinal center of lymph node><T-Cell Development><T-Cell Ontogeny><T-Lymphocyte Development><T4 Cells><T4 Lymphocytes><TLR7><TLR7 gene><Tail><Testing><Toll-Like Receptor 7><Transcription><Transcription Factor Proto-Oncogene><Transcription Repression><Transcription factor genes><Transcriptional Repression><Untranslated RNA><Vaccination><Vaccines><Work><Wuhan coronavirus><ZNF51><ZNF51 Gene><Zinc Finger Protein 51 Gene><acquired immune system><activated B cells><antibody-based immunity><bacteria pathogen><bacterial pathogen><biological signal transduction><cell motility><cell sorting><cellular differentiation><cellular reprogramming><coronavirus disease 2019 virus><coronavirus disease-19 virus><develop a vaccine><develop vaccines><development of a vaccine><developmental><epigenetically><gene modification><gene repression><genetically modified><hCoV19><histone H3 methyltransferase><histone methylase><histone methyltransferase><histone modification><immunogen><improved><in vivo><influenzavirus><living system><lymph gland><lymph nodes><lymphnodes><migration><mouse model><murine model><nCoV2><noncoding><pathogen><pathogenic bacteria><pathogenic virus><pathway><plasma cell differentiation><receptor><recruit><response><social role><transcription factor><transcriptomics><vaccine development><viral pathogen><virus pathogen>