Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Català-Moll, Francesc; Weichenhan, Dieter; Lutsik, Pavlo; Álvarez-Prado, Ángel F.; Rodríguez-Ubreva, Javier; Klemann, Christian; Speckmann, Carsten; Abolhassani, Hassan; Martínez-Gallo, Mónica; Dieli-Crimi, Romina; Soler‐Palacín, Pere; Kracker, Sven; Hammarström, Lennart; Durandy, Anne; Grimbacher, Bodo; Plass, Christoph; Ballestar, Esteban

doi:10.1101/737908

Cited by 2 publications

(2 citation statements)

References 84 publications

(104 reference statements)

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“…Differences in methylation patterns between NFKB1 mutation carriers and WT were considered relevant when loci (β-values) were 10% or more differentially methylated, with an FDR of <0.05. We observed gradual global demethylation on B cells from the naïve to the memory compartment in healthy individuals, as previously reported 69–72 . Differences in the global methylation pattern were evident at the transition from the naïve, to the IgM-, and switched memory compartments.…”

Section: Resultssupporting

confidence: 89%

Integrated Multi-omics Analyses of NFKB1 patients B cells points towards an up regulation of NF-κB network inhibitors

Camacho-Ordóñez

Ramirez

Posadas-Cantera

et al. 2022

Preprint

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The transcription factor NF-κB plays a pivotal role in the adaptive immune response. Pathogenic variants inNFKB1are the most common genetic etiology of common variable immunodeficiency (CVID). Patients frequently present with impaired terminal B cell differentiation, autoimmunity, and hyperinflammatory immune dysregulation. NF-κB signaling and target gene expression are expected to be dysregulated inNFKB1-mutated patients. Here, we performed a multi-omics characterization of B cells from a cohort of clinically affected and unaffectedNFKB1mutation carriers. Our analysis identified specific epigenetic dysregulation and gene expression differences on B cells fromNFKB1-mutated patients. We observed an aberrant expression of negative regulators of NF-κB signaling inNFKB1mutation carriers, which may be a key factor for the autoinflammatory phenotype of these patients. Moreover, our analysis points towards a dysregulation ofXBP1andBCL3, key players of B cell activation and proliferation at different stages of B cell differentiation. The reduced expression of negative regulators of the NF-κB network is likely to be one of several mechanisms responsible for the aberrant NF-κB signaling, which impairs the maintenance of a normal humoral immune response. In summary, our findings highlight epigenetic and gene expression changes in B cells associated withNFKB1mutations. Our data give insight into future therapeutic opportunities for patients withNFKB1(haplo)insufficiency.

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Section: Resultssupporting

confidence: 89%

Integrated Multi-omics Analyses of NFKB1 patients B cells points towards an up regulation of NF-κB network inhibitors

Camacho-Ordóñez

Ramirez

Posadas-Cantera

et al. 2022

Preprint

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“…In addition to these mechanisms, AID, which is sensitive to methylated C, has been proposed to play a role in active demethylation by deamination of 5meC and 5hmeC [41], although the evidence is contradictory, meaning that further studies are needed to settle the matter [42]. However, AID deficiency in humans causes overstimulation of B cell proliferation, leading to aberrant DNA methylation and gene expression profiles in naïve and memory B cells [43].…”

Section: B Cellsmentioning

confidence: 99%

Understanding the Relevance of DNA Methylation Changes in Immune Differentiation and Disease

Calle-Fabregat

Morante-Palacios

Ballestar

2020

Genes

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Immune cells are one of the most complex and diverse systems in the human organism. Such diversity implies an intricate network of different cell types and interactions that are dependently interconnected. The processes by which different cell types differentiate from progenitors, mature, and finally exert their function requires an orchestrated succession of molecular processes that determine cell phenotype and function. The acquisition of these phenotypes is highly dependent on the establishment of unique epigenetic profiles that confer identity and function on the various types of effector cells. These epigenetic mechanisms integrate microenvironmental cues into the genome to establish specific transcriptional programs. Epigenetic modifications bridge environment and genome regulation and play a role in human diseases by their ability to modulate physiological programs through external stimuli. DNA methylation is one of the most ubiquitous, stable, and widely studied epigenetic modifications. Recent technological advances have facilitated the generation of a vast amount of genome-wide DNA methylation data, providing profound insights into the roles of DNA methylation in health and disease. This review considers the relevance of DNA methylation to immune system cellular development and function, as well as the participation of DNA methylation defects in immune-mediated pathologies, illustrated by selected paradigmatic diseases.

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Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Cited by 2 publications

References 84 publications

Integrated Multi-omics Analyses of NFKB1 patients B cells points towards an up regulation of NF-κB network inhibitors

Integrated Multi-omics Analyses of NFKB1 patients B cells points towards an up regulation of NF-κB network inhibitors

Understanding the Relevance of DNA Methylation Changes in Immune Differentiation and Disease

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