Epigenetic regulation of B cell fate and function during an immune response

Zhang, Yan; Good-Jacobson, Kim L

doi:10.1111/imr.12733

Cited by 30 publications

(19 citation statements)

References 100 publications

(181 reference statements)

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“…6b, c). This is interesting given recent data showing a role for H3K27me3 in regulating germinal B cell responses (31). As seen in the naïve state, CD4 + T cells harbouring a high amount of the Kdm6b hairpin had an associated higher frequency of activated CD4 + T cells compared to those harbouring the Luciferase hairpin ( Fig.…”

Section: Kdm6b Knockdown Results In Dysregulation Of An Influenza-spesupporting

confidence: 50%

Development of a KDM6b shRNA conditional knock down mouse model

Blewitt

Dickins

Turner

2019

Preprint

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Antigen-specific CD8 + T cell differentiation in response to infection is associated with specific changes in the chromatin landscape resulting in acquisition of the lineage-specific effector functions required for pathogen clearance. Lysine (K)-specific demethylase 6B (KDM6b) is a histone demethylase that specifically recognizes and removes methyl groups from K27 tri/dimethylation on histone 3. This histone modification is associated with a repressive transcriptional state, or, in combination with the active H3K4me3 mark, a bivalent epigenetic state. Resolution of bivalency at fundamental transcription factor loci has been shown to be a key mechanism for the initiation of CD8 + T cell differentiation. To begin to address the role of KDM6b in regulating H3K27me3 demethylation in CD8 + T cell responses to infection, a model whereby KDM6b levels can be modulated is needed. To address this, we developed a conditional short hairpin RNA (shRNA) mouse model targeting KDM6b. Here we demonstrate that KDM6b knockdown results in diminished naive, CD4 + and virus-specific CD4 + and CD8 + T cell response in response to influenza A infection. To address the molecular mechanism, we demonstrate that KDM6b knockdown resulted in reduced H3K27me3 removal from the Tbx21 bivalent promoter, compared to luciferase hairpin controls. Surprisingly, this did not necessarily impact T-BET expression, or resolution of other bivalent transcription factor promoters. These data suggest that KDM6b knockdown resulting in diminished IAV-specific CD8+ T cell responses may reflect a demethylase independent function.

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Section: Kdm6b Knockdown Results In Dysregulation Of An Influenza-spesupporting

confidence: 50%

Development of a KDM6b shRNA conditional knock down mouse model

Blewitt

Dickins

Turner

2019

Preprint

View full text Add to dashboard Cite

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“…Higher levels of 5hmC prohibit cell division by maintaining cells in G1 for a longer period 10 , thus directly contributing to the balance between cell proliferation and apoptosis. Recent studies on 5hmC also revealed the complexes that form between transcription factors and epigenetic regulators during B-cell differentiation 11,12 , suggesting a potential role of 5hmC in B-cell malignancies. Therefore, profiling genome-wide 5hmC could provide insights on direct epigenetic landscape and adds additional value to the epigenetic modifications between DLBCL and FL.…”

Section: Introductionmentioning

confidence: 99%

Alterations of 5-hydroxymethylation in circulating cell-free DNA reflect molecular distinctions of subtypes of non-Hodgkin lymphoma

et al. 2021

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The 5-methylcytosines (5mC) have been implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the role of 5-hydroxymethylcytosines (5hmC) that are generated from 5mC through active demethylation, in lymphomagenesis is unknown. We profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) from 73 newly diagnosed patients with DLBCL and FL. We identified 294 differentially modified genes between DLBCL and FL. The differential 5hmC in the DLBCL/FL-differentiating genes co-localized with enhancer marks H3K4me1 and H3K27ac. A four-gene panel (CNN2, HMG20B, ACRBP, IZUMO1) robustly represented the overall 5hmC modification pattern that distinguished FL from DLBCL with an area under curve of 88.5% in the testing set. The median 5hmC modification levels in signature genes showed potential for separating patients for risk of all-cause mortality. This study provides evidence that genome-wide 5hmC profiles in cfDNA differ between DLBCL and FL and could be exploited as a non-invasive approach.

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“…CMV is known to challenge the immune system, altering the immune response to other pathogens (85). Both EBV and CMV cause a redistribution in B-cell subsets (86)(87)(88). Herpes viruses like EBV and CMV causing systemic infection of the immune system and the lifelong survival within the host with transient virus reactivation from time to time-going most often completely unnoticed and without any clinical symptoms (74, 89-96) -, are expected to leave an imprint on the immune system because of their lifelong infection of that same system.…”

Section: Discussionmentioning

confidence: 99%

Lower CMV and EBV Exposure in Children With Kawasaki Disease Suggests an Under-Challenged Immune System

et al. 2021

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Background: Kawasaki Disease (KD) is a pediatric vasculitis of which the pathogenesis is unclear. The hypothesis is that genetically pre-disposed children develop KD when they encounter a pathogen which remains most often unidentified or pathogen derived factors. Since age is a dominant factor, prior immune status in children could influence their reactivity and hence the acquisition of KD. We hypothesized that systemic immune responses early in life could protect against developing KD. With this study we tested whether the incidence of previous systemic cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection is lower in children with KD compared to healthy age-matched controls.Methods and Results: We compared 86 KD patients with an age-matched control group regarding CMV and EBV VCA IgG measurements (taken before or 9 months after IVIG treatment). We found that both CMV and EBV had an almost 2-fold lower seroprevalence in the KD population than in the control group.Conclusions: We suggest that an under-challenged immune system causes an altered immune reactivity which may affect the response to a pathological trigger causing KD in susceptible children.

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Epigenetic regulation of B cell fate and function during an immune response

Cited by 30 publications

References 100 publications

Development of a KDM6b shRNA conditional knock down mouse model

Development of a KDM6b shRNA conditional knock down mouse model

Alterations of 5-hydroxymethylation in circulating cell-free DNA reflect molecular distinctions of subtypes of non-Hodgkin lymphoma

Lower CMV and EBV Exposure in Children With Kawasaki Disease Suggests an Under-Challenged Immune System

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