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B cell differentiation is limited by de novo DNA methylation [RRBS]

ABSTRACT: B cells provide humoral immunity by differentiating into antibody-secreting plasma cells, a process that requires cell division and is linked to DNA hypomethylation and gene regulation. Conversely, accumulation of DNA methylation in B cell differentiation is less apparent. To determine the role of de novo DNA methylation in B cell differentiation, the de novo DNA methyltransferases, Dnmt3a and Dnmt3b, were deleted in B cells resulting in phenotypically normal B cell development in the bone marrow, spleen and lymph nodes. However, upon immunologic challenge, mice deficient for Dnmt3a and Dnmt3b (Dnmt3-deficient) accumulated more antigen-specific B cells and bone marrow chimeras showed this was cell-autonomous. Additionally, a five-fold increase in splenic and bone marrow plasma cells was observed. Molecular analysis revealed that Dnmt3-deficient bone marrow plasma cells failed to repress gene expression to the same level as their Dnmt3ab-sufficient counterparts. This was coupled with a failure of Dnmt3-deficient germinal center B cells and plasma cells to gain and/or maintain DNA methylation at several thousand loci that were clustered in enhancers of genes that function in B cell activation and homing. Analysis of chromatin accessibility showed Dnmt3-deficient plasma cells had increased accessibility at several genes involved in hematopoiesis and B cell differentiation. These data show that de novo DNA methylation limits B cell activation, proliferation and differentiation, and support a model whereby DNA methylation represses the aberrant transcription of genes silenced in B cell differentiation to maintain plasma cell homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE89467 | GEO | 2017/12/31

SECONDARY ACCESSION(S): PRJNA352268

REPOSITORIES: GEO

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Project description:We have used genome-wide methylation microarrays to analyze differences in CpG methylation patterns in cells relevant to the pathogenesis of myeloma plasma cells, including B cells, normal plasma cells, MGUS, presentation myeloma, and plasma cell leukemia (PCL). We show that methylation patterns in these cell types are capable of distinguishing non-malignant from malignant cells and that the main reason for this difference is hypomethylation of the genome at the transition from MGUS to presentation myeloma. In addition, gene-specific hypermethylation was evident at the myeloma stage. Differential methylation was also evident at the transition from myeloma to PCL with re-methylation of the genome, specifically of genes involved in cell-cell signaling and cell adhesion, which may contribute to independence from the bone marrow microenvironment. There was a high degree of methylation variability within presentation myeloma samples and this was associated with the cytogenetic differences between samples. More specifically, we found that methylation subgroups were defined by translocations and hyperdiploidy, with t(4;14) myeloma having the largest impact on DNA methylation. Two groups of hyperdiploid samples were identified, based on unsupervised clustering, which had an impact on overall survival. Overall, DNA methylation has a large impact on disease progression and on myeloma cytogenetic subgroups. Bone marrow aspirates were obtained after informed consent. B cells (n=6) from normal individuals were selected from peripheral blood using CD19. Plasma cells (PC) from non-myeloma patients (normal plasma cell controls, n=3) as well as MGUS (n=4) and presentation myeloma patients (n=161) were selected to a purity of >90% using CD138 microbeads and magnet-assisted cell sorting (Miltenyi Biotech, Bisley, UK). Samples from PCL patients (n=7) were not CD138 selected but contained >90% plasma cell infiltration as determined by microscopy. In order to achieve a sufficient quantity of DNA some normal plasma cell control samples were pooled.

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B cell differentiation is limited by de novo DNA methylation [RRBS]

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