Epigenetic gene regulation in B and T lymphocytes and its role in cellular activation, differentiation, and autoimmune disease Restricted; Files Only
Rose, James (Summer 2024)
Abstract
Nearly all eukaryotic cells, including lymphocytes of the adaptive immune system, regulate gene expression in part through epigenetic mechanisms. Complex networks of genes, transcription factor proteins, and epigenetic modulators work together to control how a cell reacts to its environment, undergoes prescribed cellular development, and ultimately perform functions necessary to sustain multicellular life. Here we apply a genome-wide analysis of transcript expression as well as the epigenetic landscapes of B and T cells in two different contexts. First, this work delves into the distinct transcriptomic and epigenomic profiles of human memory T cell subsets (TCM, TEM, and TEMRA). Through RNA sequencing and chromatin accessibility assays, this work reveals a progressive gradient of gene expression and chromatin changes from naïve to memory subsets. Key findings include the identification of metabolic adaptations and the role of transcription factors in mediating specific epigenetic changes—termed patterned accessibility regions—which enhance memory T cells' responsiveness to antigen re-encounters. These results highlight how epigenetic remodeling supports the specialized functions of memory T cell subsets, offering potential targets for enhancing vaccine efficacy and developing immunotherapies that leverage these epigenetic modifications. Next, we focus on B cells involved in systemic lupus erythematosus (SLE), a chronic autoimmune disease characterized by inflammation and autoantibody production. This chapter examines the epigenetic landscape of resting naïve (rN) B cells in SLE patients, comparing active and inactive disease. We identify persistent epigenetic alterations in IFN response genes and transcriptional differences in activation and cytokine signaling pathways, even during disease remission. These findings suggest that lasting epigenetic reprogramming in B cells occurs during the progression of SLE and suggests disease activity as one factor capable of modulating the previously described molecular signatures of this autoimmune disease. Finally, we expand this work by looking for such signatures in other autoimmune diseases. Much of the SLE signature in rN B cells appears to be unique to this disease, with some modest shared aspects detected in this cell type isolated from diseases such as ANCA Associated Vasculitis (AAV) and Dermatomyositis. Ultimately this work reveals aspects of the system-wide epigenetic regulation involved in lymphocyte function and its impact on normal immune responses as well as their dysregulation during autoimmune diseases.
Table of Contents
Chapter 1: Introduction 9
The discovery of lymphocytes & their role in adaptive immunity 10
The activation of lymphocytes 11
The adaptive lymphocyte receptors 11
B cell activation 12
T cell activation 14
Lymphocyte differentiation & memory 15
Effector cells 16
Memory cells 17
Epigenetic control of lymphocyte gene expression 19
Epigenetics at the molecular and system scale 19
Epigenetics in lymphocyte differentiation 21
Epigenetics in immune memory 24
Autoimmune disease & lymphocyte tolerance 26
Autoimmunity 26
B cell tolerance and autoreactivity 27
Epigenetics in autoimmune disease 29
Dissertation overview 31
Chapter 2: Distinct transcriptomic and epigenomic modalities underpin human memory T cell subsets and their activation potential 33
Abstract 34
Introduction 34
Results 36
The shared transcriptional programs of human CD4+and CD8+ MTC 36
Resting TEM/TEMRA cells exhibit progressively greater transcriptional differentiation from naïve progenitors than TCM 39
MTC subsets exhibit distinct migration and metabolism characteristics 42
The chromatin landscape of memory subsets correlates with transcriptional differentiation 46
Differentiated chromatin between MTC subsets is enriched for bZIP, HMG, T-box, and bHLH transcription factor motifs 49
bHLH Family Factors AHR and HIF1A potentially regulate different environmental responses in CD8+ TCM and TEM MTC subsets 52
Genes that are uniquely upregulated in stimulated memory subset cells include Induced and Augmented transcripts 55
Augmented gene expression is correlated with epigenetic changes introduced by earlier activation of naïve cells 58
PAR contain distinct sets of transcription factor motifs that segregate T cells by lineage and memory subtype 61
Discussion 64
Methods 70
Supporting Data 78
Chapter 3: Clinically inactive SLE resting naïve B cells retain distinct transcriptomes and alterations to the epigenome 94
Abstract 95
Introduction 96
Results 98
Resting and activated B cell subtypes are altered by SLE disease and disease activity 98
SLE rN B cells express an abnormal transcriptome in patients with low disease activity 102
Type I IFN response genes, TLR, and BCR signaling genes differentiate rN B cells in active SLE 103
Alternative cytokine signaling gene expression distinguishes inactive SLE 106
Epigenetic alterations to IFN response and TLR regulation loci remain accessible during disease remission 110
Unique and shared transcription factor motifs in inactive and active SLE epigenomes 113
MEF2C and E2A/E2-2 factors likely regulate inactive SLE specific gene sets 115
Discussion 117
Methods 123
Supporting Data 128
Chapter 4: Work in progress 142
Introduction 143
Results & Discussion 144
Supporting Data 150
Chapter 5: Discussion 153
References 161
About this Dissertation
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File download under embargo until 21 August 2026 | 2024-08-09 13:47:34 -0400 | File download under embargo until 21 August 2026 |
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