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B1a and B2 cells are characterized by distinct CpG modification states at DNMT3A-maintained enhancers

Author

Listed:
  • Vinay S. Mahajan

    (Ragon Institute of MGH, MIT, and Harvard
    Brigham and Women’s Hospital)

  • Hamid Mattoo

    (Ragon Institute of MGH, MIT, and Harvard
    Immunology and Inflammation Therapeutic Area, Sanofi)

  • Na Sun

    (Ragon Institute of MGH, MIT, and Harvard
    Department of Electrical Engineering and Computer Science, MIT)

  • Vinayak Viswanadham

    (Ragon Institute of MGH, MIT, and Harvard
    Harvard Medical School)

  • Grace J. Yuen

    (Ragon Institute of MGH, MIT, and Harvard)

  • Hugues Allard-Chamard

    (Ragon Institute of MGH, MIT, and Harvard)

  • Maimuna Ahmad

    (Ragon Institute of MGH, MIT, and Harvard)

  • Samuel J. H. Murphy

    (Ragon Institute of MGH, MIT, and Harvard)

  • Annaiah Cariappa

    (Ragon Institute of MGH, MIT, and Harvard)

  • Yesim Tuncay

    (Ragon Institute of MGH, MIT, and Harvard)

  • Shiv Pillai

    (Ragon Institute of MGH, MIT, and Harvard)

Abstract

The B1 and B2 lineages of B cells contribute to protection from pathogens in distinct ways. The role of the DNA CpG methylome in specifying these two B-cell fates is still unclear. Here we profile the CpG modifications and transcriptomes of peritoneal B1a and follicular B2 cells, as well as their respective proB cell precursors in the fetal liver and adult bone marrow from wild-type and CD19-Cre Dnmt3a floxed mice lacking DNMT3A in the B lineage. We show that an underlying foundational CpG methylome is stably established during B lineage commitment and is overlaid with a DNMT3A-maintained dynamic methylome that is sculpted in distinct ways in B1a and B2 cells. This dynamic DNMT3A-maintained methylome is composed of novel enhancers that are closely linked to lineage-specific genes. While DNMT3A maintains the methylation state of these enhancers in both B1a and B2 cells, the dynamic methylome undergoes a prominent programmed demethylation event during B1a but not B2 cell development. We propose that the methylation pattern of DNMT3A-maintained enhancers is determined by the coincident recruitment of DNMT3A and TET enzymes, which regulate the developmental expression of B1a and B2 lineage-specific genes.

Suggested Citation

  • Vinay S. Mahajan & Hamid Mattoo & Na Sun & Vinayak Viswanadham & Grace J. Yuen & Hugues Allard-Chamard & Maimuna Ahmad & Samuel J. H. Murphy & Annaiah Cariappa & Yesim Tuncay & Shiv Pillai, 2021. "B1a and B2 cells are characterized by distinct CpG modification states at DNMT3A-maintained enhancers," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22458-9
    DOI: 10.1038/s41467-021-22458-9
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