Developmental regulation of DNA cytosine methylation at the immunoglobulin heavy chain constant locus

PLoS Genet. 2019 Feb 19;15(2):e1007930. doi: 10.1371/journal.pgen.1007930. eCollection 2019 Feb.


DNA cytosine methylation is involved in the regulation of gene expression during development and its deregulation is often associated with disease. Mammalian genomes are predominantly methylated at CpG dinucleotides. Unmethylated CpGs are often associated with active regulatory sequences while methylated CpGs are often linked to transcriptional silencing. Previous studies on CpG methylation led to the notion that transcription initiation is more sensitive to CpG methylation than transcriptional elongation. The immunoglobulin heavy chain (IgH) constant locus comprises multiple inducible constant genes and is expressed exclusively in B lymphocytes. The developmental B cell stage at which methylation patterns of the IgH constant genes are established, and the role of CpG methylation in their expression, are unknown. Here, we find that methylation patterns at most cis-acting elements of the IgH constant genes are established and maintained independently of B cell activation or promoter activity. Moreover, one of the promoters, but not the enhancers, is hypomethylated in sperm and early embryonic cells, and is targeted by different demethylation pathways, including AID, UNG, and ATM pathways. Combined, the data suggest that, rather than being prominently involved in the regulation of the IgH constant locus expression, DNA methylation may primarily contribute to its epigenetic pre-marking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cell Lineage / genetics
  • Cell Lineage / immunology
  • CpG Islands / genetics
  • Cytosine / metabolism
  • DNA Methylation*
  • Epigenesis, Genetic
  • Gene Expression Regulation, Developmental
  • Genes, Immunoglobulin Heavy Chain*
  • Immunoglobulin Constant Regions / genetics*
  • Immunoglobulin Heavy Chains / genetics*
  • Lymphocyte Activation / genetics
  • Mice
  • Promoter Regions, Genetic


  • Immunoglobulin Constant Regions
  • Immunoglobulin Heavy Chains
  • Cytosine

Grant support

This work was supported by the Agence Nationale de la Recherche [grant ANR-16-CE12-0017]; the Institut National du Cancer [grant INCA_9363, PLBIO15134]; the Fondation ARC pour la Recherche sur le cancer [PJA 20141201647] The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.