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

Autor: Fatima-Zohra Braikia, Joana M. Santos, Audrey Dauba, Ahmed Amine Khamlichi, Chloé Oudinet
Přispěvatelé: LIttoral ENvironnement et Sociétés - UMRi 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Tours (UT)
Rok vydání: 2019
Předmět:
Cancer Research
B Cells
[SDV]Life Sciences [q-bio]
QH426-470
Lymphocyte Activation
Biochemistry
Epigenesis
Genetic
Mice
White Blood Cells
0302 clinical medicine
Animal Cells
Medicine and Health Sciences
Promoter Regions
Genetic
[SDV.BDD]Life Sciences [q-bio]/Development Biology
Genetics (clinical)
Genetics
Regulation of gene expression
B-Lymphocytes
0303 health sciences
DNA methylation
Nucleotides
Organic Compounds
Gene Expression Regulation
Developmental
Methylation
Chromatin
Nucleic acids
Chemistry
[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology
CpG site
Regulatory sequence
Physical Sciences
[SDV.IMM]Life Sciences [q-bio]/Immunology
Epigenetics
Cellular Types
Immunoglobulin Constant Regions
Immunoglobulin Heavy Chains
DNA modification
Chromatin modification
Research Article
Chromosome biology
Cell biology
Genes
Immunoglobulin Heavy Chain
Immune Cells
Immunology
DNA transcription
Biology
Cytosine
03 medical and health sciences
Animals
Cell Lineage
Antibody-Producing Cells
Molecular Biology
Gene
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Blood Cells
Biology and life sciences
Organic Chemistry
Chemical Compounds
Promoter
DNA
Sperm
Germ Cells
Pyrimidines
Genetic Loci
CpG Islands
Gene expression
030217 neurology & neurosurgery
Zdroj: PLoS Genetics
PLoS Genetics, Vol 15, Iss 2, p e1007930 (2019)
PLoS Genetics, Public Library of Science, 2019, 15 (2), pp.e1007930. ⟨10.1371/journal.pgen.1007930⟩
ISSN: 1553-7404
1553-7390
Popis: 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.
Author summary DNA methylation mainly occurs at CpG dinucleotides and strongly influences gene expression during development. Deregulation of DNA methylation is often associated with disease. In mammalian genomes, unmethylated CpG dinucleotides are generally associated with active regulatory sequences, while methylated CpGs are often associated with silent promoters. The immunoglobulin heavy chain constant locus comprises multiple inducible constant genes and is expressed exclusively in B lymphocytes. We show that methylation patterns of most of the locus cis-elements, including promoters, enhancers and insulators, are established and faithfully maintained independently of B cell activation or transcription initiation. Acquisition of DNA methylation by the constant genes exons occurs independently of transcriptional elongation. One late B cell specific promoter is hypomethylated early in ontogeny. Constant genes promoters recruit different demethylation pathways that become dispensable for the maintenance of the mark in the B cell lineage. The data suggest that, rather than playing a prominent role in transcriptional regulation, DNA methylation may contribute to the epigenetic pre-marking of the IgH constant locus.
Databáze: OpenAIRE
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