Plasma cell differentiation is coupled to division-dependent DNA hypomethylation and gene regulation

Nat Immunol. 2016 Oct;17(10):1216-1225. doi: 10.1038/ni.3519. Epub 2016 Aug 8.


The epigenetic processes that regulate antibody-secreting plasma cells are not well understood. Here, analysis of plasma cell differentiation revealed DNA hypomethylation of 10% of CpG loci that were overrepresented at enhancers. Inhibition of DNA methylation enhanced plasma cell commitment in a cell-division-dependent manner. Analysis of B cells differentiating in vivo stratified by cell division revealed a fivefold increase in mRNA transcription coupled to DNA hypomethylation. Demethylation occurred first at binding motifs for the transcription factors NF-κB and AP-1 and later at those for the transcription factors IRF and Oct-2 and was coincident with activation and differentiation gene-expression programs in a cell-division-dependent manner. These data provide mechanistic insight into cell-division-coupled transcriptional and epigenetic reprogramming and suggest that DNA hypomethylation reflects the cis-regulatory history of plasma cell differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / physiology*
  • Binding Sites / genetics
  • Cell Differentiation / genetics
  • Cell Division / genetics
  • Cells, Cultured
  • CpG Islands / genetics
  • DNA Methylation*
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation
  • Immunity, Humoral / genetics
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Octamer Transcription Factor-2 / genetics
  • Octamer Transcription Factor-2 / metabolism
  • Plasma Cells / physiology*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*


  • Interferon Regulatory Factors
  • NF-kappa B
  • Octamer Transcription Factor-2
  • Transcription Factor AP-1