Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
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.
DNA 胞嘧啶甲基化参与发育过程中基因表达的调控，其失调通常与疾病有关。哺乳动物基因组在 CpG 二核苷酸处主要被甲基化。未甲基化的 CpG 通常与活跃的调控序列相关，而甲基化的 CpG 通常与转录沉默相关。先前关于 CpG 甲基化的研究表明，转录起始比转录延伸对 CpG 甲基化更为敏感。免疫球蛋白重链（IgH）恒定基因座包含多个可诱导的恒定基因，仅在 B 淋巴细胞中表达。IgH 恒定基因的甲基化模式在 B 细胞发育阶段建立，以及 CpG 甲基化在其表达中的作用尚不清楚。在这里，我们发现 IgH 恒定基因的大多数顺式作用元件的甲基化模式是独立于 B 细胞激活或启动子活性建立和维持的。此外，一个启动子（而不是增强子）在精子和早期胚胎细胞中呈低甲基化状态，并且受到不同的去甲基化途径的靶向，包括 AID、UNG 和 ATM 途径。综合这些数据表明，DNA 甲基化可能主要有助于其表观遗传预标记，而不是显著参与 IgH 恒定基因座表达的调控。
