Epigenetic gene regulation in plasma cells

Patterson, Dillon G.; Kania, Anna; Zuo, Zhihong; Scharer, Christopher D.; Boss, Jeremy M.

doi:10.1111/imr.12975

Cited by 12 publications

(11 citation statements)

References 185 publications

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“…Cell division is tightly linked to ASC formation, with transcriptional and epigenetic reprogramming (2023) occurring as the cells divide (17,2426). As such, each cellular division represents a distinct stage during B cell differentiation, with ASC formation occurring after at least eight cell divisions (17,25,27,28). Cell-extrinsic signals can impact the specific division in which differentiation occurs, but the molecular programming events leading to ASC remain the same (17).…”

Section: An Irf4mycmtorc1 Integrated Pathway Controls Cell Growth And...mentioning

confidence: 99%

An IRF4–MYC–mTORC1 Integrated Pathway Controls Cell Growth and the Proliferative Capacity of Activated B Cells during B Cell Differentiation In Vivo

Patterson

Kania

Price

et al. 2021

The Journal of Immunology

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Cell division is an essential component of B cell differentiation to Ab-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, 4-hydroxy-3-nitrophenylacetyl–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 cells 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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Section: An Irf4mycmtorc1 Integrated Pathway Controls Cell Growth And...mentioning

confidence: 99%

An IRF4–MYC–mTORC1 Integrated Pathway Controls Cell Growth and the Proliferative Capacity of Activated B Cells during B Cell Differentiation In Vivo

Patterson

Kania

Price

et al. 2021

The Journal of Immunology

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“…The malaria infections had revealed an important role for ROCK1 in regulating the ability of B cells to respond to heme and upregulate a heme metabolism signature, a pathway recently recognized to be important in controlling B cell fate outcomes 7,8 . This led us to explore whether ROCK1 could regulate Bach2, a heme-regulated transcription factor that not only controls key 9 heme metabolic enzymes like Hmox1 but also promotes the GC program and prevents premature PC differentiation by repressing Blimp1 expression 9 .…”

Section: Rock1 Regulates the Heme-sensing Transcription Factor Bach2mentioning

confidence: 99%

ROCK1 orchestrates B cell differentiation in response to PAMPs and heme by controlling the heme-regulated proteins Bach2 and HRI

Rivera-Correa,

Gupta,

Ricker

et al. 2023

Preprint

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Protective humoral responses require that B cells successfully complete their differentiation programs even when exposed to hostile environments generated during severe infections, like the massive hemolysis triggered by malaria. The mechanisms utilized by differentiating B cells to withstand damaging conditions replete in PAMPs and DAMPs are poorly understood. Here we demonstrate that the serine-threonine kinase ROCK1 enables B cells to execute their differentiation programs upon exposure to PAMPs and high levels of heme, a critical DAMP, by controlling two key heme-regulated molecules, Bach2 and HRI. ROCK1 restrains plasma cell differentiation by phosphorylating Bach2. As B cells differentiate in the presence of PAMPs and heme, furthermore, ROCK1 limits the proinflammatory potential of B cells and restrains mTORC1 activity by controlling the assembly of multimolecular complexes that contain the adaptor p62, raptor, ripoptosome components, and molecules involved in RNA metabolism and proteostasis. ROCK1 regulates formation of these complexes by controlling the interplay between HSPs and the stress kinase HRI. Thus, ROCK1 helps B cells cope with intense pathogen-driven destruction by coordinating the activity and localization of key molecules that mediate cell-fate decisions, effector functions, and RNA and protein homeostasis. These ROCK1-dependent mechanisms may be widely employed by cells to handle severe environmental stresses and these findings may be broadly relevant for infections, vaccine development, and immune-mediated diseases marked by chronic tissue damage like autoimmune disorders.

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“…First, the rapid death of ASC ex vivo limits deep investigation into their proliferation profiles. While the time to first division in naïve B cells is typically 24-36h 4,5,36,37 , observation of cell division in vitro requires viability for at least 48-72h. The problem studying blood and BM ASC was the rapid apoptosis within hours 21,[38][39][40] .…”

Section: Challenges Of Assessing Proliferation Status Of Human Asc Pr...mentioning

confidence: 99%

Majority of human circulating plasmablasts stop blasting: A probable misnomer

Nguyen,

Saney,

Hentenaar

et al. 2023

Preprint

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Following infection or vaccination, early-minted antibody secreting cells (ASC) or plasmablasts appear in circulation transiently, and a small fraction migrates to the spleen or bone marrow (BM) to mature into long-lived plasma cells (LLPC). While LLPC, by definition, are quiescent or non-dividing, the majority of blood ASC are thought to be “blasting” or proliferative. In this study, we find >95% nascent blood ASC in culture express Ki-67 but only 6-12% incorporate BrdU after 4h or 24h labeling. In contrast, <5% BM LLPC in culture are Ki-67+with no BrdU uptake. Due to limitations of traditional flow cytometry, we utilized a novel optofluidic technology to evaluate cell division with simultaneous functional Ig secretion. We find 11% early-minted blood ASC undergo division, and none of the terminally differentiated BM LLPC (CD19-CD38hiCD138+) divide during the 7-21 days in culture. While BM LLPC undergo complete cell cycle arrest, the process of differentiation into an ASC of plasmablasts discourages entry into S phase. Since the majority of Ki-67+nascent blood ASC have exited cell cycle and are no longer actively “blasting”, the term “plasmablast”, which traditionally refers to an ASC that still has the capacity to divide, may probably be a misnomer.

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Epigenetic gene regulation in plasma cells

Cited by 12 publications

References 185 publications

An IRF4–MYC–mTORC1 Integrated Pathway Controls Cell Growth and the Proliferative Capacity of Activated B Cells during B Cell Differentiation In Vivo

An IRF4–MYC–mTORC1 Integrated Pathway Controls Cell Growth and the Proliferative Capacity of Activated B Cells during B Cell Differentiation In Vivo

ROCK1 orchestrates B cell differentiation in response to PAMPs and heme by controlling the heme-regulated proteins Bach2 and HRI

Majority of human circulating plasmablasts stop blasting: A probable misnomer

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