Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival

Alexander, Lou-Ella M.M.; Watters, January M.; Reusch, Jessica A.; Maurin, Michelle; Nepon-Sixt, Brook S.; Vrzalikova, Katerina; Alexandrow, Mark G.; Murray, Paul G.; Wright, Kenneth L.

doi:10.1016/j.molimm.2017.08.016

“…Indeed, BLIMP1 has been previously demonstrated to control IL-10 induction in T cells 47 , and in a recent study in regulatory B cells 48 . Analysis of publicly available ChIP-seq datasets in both mouse and human B cells are in line with this finding, suggesting that IL-10 is a significantly enriched target of BLIMP1 33,49 . This observation is reminiscent of recent work highlighting the role for BLIMP1-expressing regulatory plasmablasts and plasma cells in vivo 3,4,50,51 , but also in humans ex vivo 51 .…”

Section: Discussionsupporting

confidence: 61%

Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

Bibby

¹

,

Purvis

²

,

Hayday

³

et al. 2020

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Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.

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“…Downstream of TLR9 ligation, BLIMP1 was shown to positively regulate IL-10 expression, suggesting its role as a transcriptional regulator of IL-10 in human B cells. Analysis of publicly available ChIP-seq datasets in both murine and human B cells are in line with this finding, suggesting that IL-10 is a significantly enriched target of BLIMP1 32,45 . This observation is reminiscent of recent 305 work highlighting the role for BLIMP1-expressing regulatory plasmablasts and plasma cells in vivo 3,4,46,47 , but also in humans ex vivo 47 .…”

supporting

confidence: 60%

Cholesterol metabolism drives regulatory B cell function

Bibby

¹

,

Purvis

²

,

Hayday

³

et al. 2020

Preprint

1

0

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Regulatory B cells restrict immune and inflammatory responses across a number of contexts. Thiscapacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven 25 by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) was required to specifically drive IL-10 production, and to attenuate Th1 responses.Furthermore, GGPP-dependent protein modifications controlled signaling through PI3Kd-AKT-GSK3, which in turn promoted BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome, termed mevalonate kinase 30 deficiency (MKD). Consistent with our findings, B cells from MKD patients induced poor IL-10 responses and were functionally impaired. Moreover, metabolic supplementation with GGPP was able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells. 40Comparable suppressive activity has been demonstrated in human regulatory B cells in vitro, suggesting that these cells also contribute toward regulating inflammatory responses in humans 5,6 . In support of this, IL-10 producing B cells have been demonstrated to be numerically depleted or functional impaired, ex vivo, in patients with inflammatory disease 5,11,12 . 45Despite the importance of IL-10 production by B cells, relatively little is known about the molecular mechanisms that govern its expression. Typically, induction of a regulatory phenotype in both human and murine B cells has been achieved through ligation of TLR9 or CD40 5,6,13 . Downstream, PI3K and ERK signals appear to be important for IL-10 expression 14,15 . This is in broad agreement with in vivo data from mouse models suggesting that both TLR and CD40 signals are required for the induction of 50 IL-10 in response to inflammatory stimuli 3,13 . However, precise details of the signaling cascades or cellular profiles underpinning the induction of a regulatory program in B cells are poorly understood.Control of immune cell metabolism is critical in regulating fundamental immunological processes 16,17 . However, in comparison to innate cell and T cell lineages, there has been relatively little work 55 aimed at understanding the metabolic regulation of B cell biology [18][19][20] . Furthermore, there is currently no understanding toward the metabolic requirements of regulatory B cells. An emerging concept from studies of regulatory T cells and M2 macrophages is their heightened reliance on lipid metabolism in comparison to the metabolic requirements of inflammatory immune cell lineages. Much of this work has focused on fatty acid oxidation, defining this as a central pathway that underpins polarization and 60 effector functions in regulatory cells 21 . In contrast, the contribution of cholesterol metabolism (the multi-step conversion of HM...

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“…Exploiting three additional ChiP-Seq datasets (GSM1668937 [ 39 ], GSM2735456 [ 40 ], GSM803334 [ 38 ]), we identified direct ETS1 targets that overlap with genes regulated by BCL6, BLIMP1, and PAX5, three transcription factors that are also important for normal and neoplastic B cells ( Figure 3 ; Table S3 ). Among the 97 positively regulated direct ETS1 targets, the greatest overlap was with PAX5 targets (80%), followed by BCL6 (49%): 41% of the 97 ETS1 targets were targeted by both PAX5 and BCL6.…”

Section: Resultsmentioning

confidence: 99%

“…As already mentioned, other transcription factors important for normal and neoplastic B cells are BCL6, BLIMP1, and PAX5. The integration of ETS1 data with publicly available ChiP-Seq datasets [ 38 , 39 , 40 ] indicates that there is a high overlap of the ETS1 transcriptional network with genes regulated by these other three transcriptional factors, and especially with PAX5. This is in strong agreement with the notion that ETS1 and PAX5 closely interact at the DNA level to perform their regulatory activity [ 46 , 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Role of ETS1 in the Transcriptional Network of Diffuse Large B Cell Lymphoma of the Activated B Cell-Like Type

Priebe

¹

,

Sartori

²

,

Napoli

³

et al. 2020

Cancers

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Diffuse large B cell lymphoma (DLBCL) is a heterogenous disease that has been distinguished into at least two major molecular entities, the germinal center-like B cell (GCB) DLBCL and activated-like B cell (ABC) DLBCL, based on transcriptome expression profiling. A recurrent ch11q24.3 gain is observed in roughly a fourth of DLBCL cases resulting in the overexpression of two ETS transcription factor family members, ETS1 and FLI1. Here, we knocked down ETS1 expression by siRNA and analyzed expression changes integrating them with ChIP-seq data to identify genes directly regulated by ETS1. ETS1 silencing affected expression of genes involved in B cell signaling activation, B cell differentiation, cell cycle, and immune processes. Integration of RNA-Seq (RNA sequencing) data and ChIP-Seq (chromatin immunoprecipitation sequencing) identified 97 genes as bona fide, positively regulated direct targets of ETS1 in ABC-DLBCL. Among these was the Fc receptor for IgM, FCMR (also known as FAIM3 or Toso), which showed higher expression in ABC- than GCB-DLBCL clinical specimens. These findings show that ETS1 is contributing to the lymphomagenesis in a subset of DLBCL and identifies FCMR as a novel target of ETS1, predominantly expressed in ABC-DLBCL.

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Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival

Cited by 19 publications

References 79 publications

Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

Cholesterol metabolism drives regulatory B cell function

Role of ETS1 in the Transcriptional Network of Diffuse Large B Cell Lymphoma of the Activated B Cell-Like Type

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