Conserved epigenetic programming and enhanced heme metabolism drive memory B cell reactivation

Price, Madeline J.; Scharer, Christopher D.; Kania, Anna; Randall, Troy D.; Boss, Jeremy M.

doi:10.1101/2021.01.20.427446

Cited by 8 publications

(13 citation statements)

References 71 publications

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“…In module 2, enhanced expression of glycolysis (GAPDH and TPI1) and IFN response (IFITM2, IFITM1, IFITM3, IFNGR2, and ISG20) genes in human COVID-19 patients, particularly severely ill patients, may promote the differentiation of unswitched memory B cells into plasmablasts (Figures 4D, E) (52). In addition, elevated levels of OXPHOS-related genes, especially in patients with severe disease, may facilitate the differentiation of memory B cells into plasma cells (Figures 4D, E) (53).…”

Section: Metabolic Rewiring Correlate With the Differentiation Immunoglobin Secretion And Survival Of Pcs And For The Differentiation Of mentioning

confidence: 99%

Single-Cell RNA Sequencing Analysis of the Immunometabolic Rewiring and Immunopathogenesis of Coronavirus Disease 2019

Zhang

Huang³

et al. 2021

Front. Immunol.

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Although immune dysfunction is a key feature of coronavirus disease 2019 (COVID-19), the metabolism-related mechanisms remain elusive. Here, by reanalyzing single-cell RNA sequencing data, we delineated metabolic remodeling in peripheral blood mononuclear cells (PBMCs) to elucidate the metabolic mechanisms that may lead to the progression of severe COVID-19. After scoring the metabolism-related biological processes and signaling pathways, we found that mono-CD14+ cells expressed higher levels of glycolysis-related genes (PKM, LDHA and PKM) and PPP-related genes (PGD and TKT) in severe patients than in mild patients. These genes may contribute to the hyperinflammation in mono-CD14+ cells of patients with severe COVID-19. The mono-CD16+ cell population in COVID-19 patients showed reduced transcription levels of genes related to lysine degradation (NSD1, KMT2E, and SETD2) and elevated transcription levels of genes involved in OXPHOS (ATP6V1B2, ATP5A1, ATP5E, and ATP5B), which may inhibit M2-like polarization. Plasma cells also expressed higher levels of the OXPHOS gene ATP13A3 in COVID-19 patients, which was positively associated with antibody secretion and survival of PCs. Moreover, enhanced glycolysis or OXPHOS was positively associated with the differentiation of memory B cells into plasmablasts or plasma cells. This study comprehensively investigated the metabolic features of peripheral immune cells and revealed that metabolic changes exacerbated inflammation in monocytes and promoted antibody secretion and cell survival in PCs in COVID-19 patients, especially those with severe disease.

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Section: Metabolic Rewiring Correlate With the Differentiation Immunoglobin Secretion And Survival Of Pcs And For The Differentiation Of mentioning

confidence: 99%

Single-Cell RNA Sequencing Analysis of the Immunometabolic Rewiring and Immunopathogenesis of Coronavirus Disease 2019

Zhang

Huang³

et al. 2021

Front. Immunol.

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“…As this analysis was performed at day 6 following infection, it is unlikely that the generation of ASC at this time point involve a full germinal center reaction. However, antigen-specific ASC can be observed at this time point (88). These data suggest that the timing of division-coupled reprogramming events needed for ASC differentiation are similar for T-independent antigens and the early differentiation process that occurs with T-dependent antigens.…”

Section: Discussionmentioning

confidence: 65%

An IRF4-MYC-mTORC1 integrated pathway controls cell growth and the proliferative capacity of activated B cells during B cell differentiationin vivo

Patterson

Kania

Price

et al. 2021

Preprint

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Cell division is an essential component of B cell differentiation to antibody-secreting plasma cells, with critical reprogramming occurring during the initial stages of B cell activation. However, a complete understanding of the factors that coordinate early reprogramming events in vivo remain to be determined. In this study, we examined the initial reprogramming by IRF4 in activated B cells using an adoptive transfer system and mice with a B cell-specific deletion of IRF4. IRF4-deficient B cells responding to influenza, NP-Ficoll and LPS divided, but stalled during the proliferative response. Gene expression profiling of IRF4-deficient B cells at discrete divisions revealed IRF4 was critical for inducing MYC target genes, oxidative phosphorylation, and glycolysis. Moreover, IRF4-deficient B cells maintained an inflammatory gene expression signature. Complementary chromatin accessibility analyses established a hierarchy of IRF4 activity and identified networks of dysregulated transcription factor families in IRF4-deficient B cells, including E-box binding bHLH family members. Indeed, B cells lacking IRF4 failed to fully induce Myc after stimulation and displayed aberrant cell cycle distribution. Furthermore, IRF4-deficient B cells showed reduced mTORC1 activity and failed to initiate the B cell-activation unfolded protein response and grow in cell size. Myc overexpression in IRF4-deficient was sufficient to overcome the cell growth defect. Together, these data reveal an IRF4-MYC-mTORC1 relationship critical for controlling cell growth and the proliferative response during B cell differentiation.

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“…Memory B cells are able to rapidly differentiate into ASC compared to antigen‐inexperienced naive B cells; however, the mechanisms that facilitate these enhanced secondary responses are not fully understood. Memory B cells were found to harbor unique epigenetic and transcriptional features with primed accessible chromatin surrounding genes important in ASC differentiation, including BLIMP1 32 . Compared to naive B cells, memory B cells upregulated their iron homeostasis metabolic pathway and possessed greater basal levels of heme, as determined using the expression of HO‐1 32 .…”

Section: Unique Biology Of a Plasma Cellmentioning

confidence: 99%

“…Memory B cells were found to harbor unique epigenetic and transcriptional features with primed accessible chromatin surrounding genes important in ASC differentiation, including BLIMP1 32 . Compared to naive B cells, memory B cells upregulated their iron homeostasis metabolic pathway and possessed greater basal levels of heme, as determined using the expression of HO‐1 32 . Treatment of mouse and human naive and memory B cells with hemin promoted ASC formation and led to an increase in both basal and maximal respiratory capacity 32 .…”

Section: Unique Biology Of a Plasma Cellmentioning

confidence: 99%

“…Compared to naive B cells, memory B cells upregulated their iron homeostasis metabolic pathway and possessed greater basal levels of heme, as determined using the expression of HO‐1 32 . Treatment of mouse and human naive and memory B cells with hemin promoted ASC formation and led to an increase in both basal and maximal respiratory capacity 32 . Although heme can act through multiple pathways to promote ASC formation (Figure 2), the results mirrored the increase in ASC observed following dichloroacetate treatment to enhance OXPHOS metabolism.…”

Section: Unique Biology Of a Plasma Cellmentioning

confidence: 99%

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Epigenetic gene regulation in plasma cells

Patterson

Kania

Zuo

et al. 2021

Immunological Reviews

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Humoral immunity provides protection from pathogenic infection and is mediated by antibodies following the differentiation of naive B cells (nBs) to antibody‐secreting cells (ASCs). This process requires substantial epigenetic and transcriptional rewiring to ultimately repress the nB program and replace it with one conducive to ASC physiology and function. Notably, these reprogramming events occur within the framework of cell division. Efforts to understand the relationship of cell division with reprogramming and ASC differentiation in vivo have uncovered the timing and scope of reprogramming, as well as key factors that influence these events. Herein, we discuss the unique physiology of ASC and how nBs undergo epigenetic and genome architectural reorganization to acquire the necessary functions to support antibody production. We also discuss the stage‐wise manner in which reprogramming occurs across cell divisions and how key molecular determinants can influence B cell fate outcomes.

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Conserved epigenetic programming and enhanced heme metabolism drive memory B cell reactivation

Cited by 8 publications

References 71 publications

Single-Cell RNA Sequencing Analysis of the Immunometabolic Rewiring and Immunopathogenesis of Coronavirus Disease 2019

Single-Cell RNA Sequencing Analysis of the Immunometabolic Rewiring and Immunopathogenesis of Coronavirus Disease 2019

An IRF4-MYC-mTORC1 integrated pathway controls cell growth and the proliferative capacity of activated B cells during B cell differentiationin vivo

Epigenetic gene regulation in plasma cells

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