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DNA methylation: Better mark the locus before it’s too late…

DNA cytosine methylation is a common epigenetic regulation mechanism in vertebrates and aberrant DNA cytosine methylation is often associated with cancer. Previous studies led to the notion that during the transcriptional cycle, transcription initiation is the most sensitive step to cytosine methylation. Researchers at the Institut de Pharmacologie et de Biologie Structurale have found that at a B cell-specific multigene locus, methylation patterns at most regulatory elements are established and maintained independently of gene expression. Some patterns are established early during embryonic development, prior to the specification of the B cell lineage, suggesting an epigenetic pre-marking of the locus. This work was published in PLoS Genetics in February 19th, 2019.  


DNA cytosine methylation is a common epigenetic regulation mechanism in vertebrates and is involved in gene expression regulation during development and differentiation as well as in defense of the genome against transposable elements. DNA methylation provides a robust epigenetic mechanism for cell fate decisions, cell identity and tissue homeostasis, and aberrant DNA cytosine methylation is often associated with disease such as cancer.
Mammalian genomes are predominantly methylated at cytosines in the context of CpG dinucleotide. Mammalian genomes are mostly CpG-poor and these CpG motifs are globally methylated. While unmethylated CpG sites are generally associated with active promoters, methylated CpGs (mCpGs) are closely associated with transcriptionally silent promoters. This pattern is less obvious when it comes to transcription elongation as mCpGs in gene body did not block elongation, leading to the notion that it is transcription initiation that is more sensitive to cytosine methylation.
By analyzing the methylation patterns of the B cell-specific immunoglobulin heavy chain constant locus at different stages of embryonic and B cell development, Oudinet et al. have found that methylation patterns at most regulatory elements of the locus are established and maintained independently of B cell activation or promoter activity. Moreover, one of the promoters is hypomethylated in sperm and early embryonic cells. Two promoters involved in specific adaptive immune responses recruit different demethylation pathways during early embryogenesis, before the appearance of B lymphocytes. These demethylation pathways become dispensable for the maintenance of the mark in the B cell lineage. These findings suggest that, rather than being prominently involved in the regulation of the constant locus expression, DNA methylation may primarily contribute to its epigenetic pre-marking for specific adaptive immune responses. 
 

 

Figure. (A). Scheme of a rearranged mouse IgH locus. The constant genes have a similar structure. Their transcription initiates at I promoters whose activity is controlled by a super-enhancer called 3’RR. +1 indicates transcription initiation sites. (B). An illustration of CpG methylation profiles of g3 et g2b constant genes. PIg3 and PIg2b promoters are unmethylated (open circles) prior to and after activation. Transcriptional elongatioon across Cg3 and Cg2b constant regions does not alter the hypermethylated pattern (filled circles) of these regions. 
© Amine Khamlichi

 

Reference

Oudinet C, Braikia FZ, Dauba A, Santos JM, Khamlichi AA. 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. PubMed PMID: 30779742.

Contact:

Researcher: Ahmed Amine Khamlichi | Amine.Khamlichi@ipbs.fr
Press: Françoise Viala | 06 01 26 52 59 | Communication@ipbs.fr