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

Chloé Oudinet (1) , Fatima-Zohra Braikia (2) , Audrey Dauba (3) , Joana M Santos , Ahmed Amine Khamlichi (4)

1 LIENSs - LIttoral ENvironnement et Sociétés
2 CRIBL - Contrôle de la Réponse Immune B et des Lymphoproliférations
3 Cellules Dendritiques, Immunomodulation et Greffes
4 IPBS - Institut de pharmacologie et de biologie structurale

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 methyla-tion 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 demethyla-tion 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.

Domaines: Immunologie; Immunité adaptative; Sciences du Vivant [q-bio]; Biologie du développement

Chloé Oudinet, Fatima-Zohra Braikia, Audrey Dauba, Joana M Santos, Ahmed Amine Khamlichi. Developmental regulation of DNA cytosine methylation at the immunoglobulin heavy chain constant locus. PLoS Genetics, 2019, 15 (2), pp.e1007930. ⟨10.1371/journal.pgen.1007930⟩. ⟨hal-02361206⟩