Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
Brigham and Women's Hospital, Boston, MA, USA.
Nat Commun. 2021 Apr 13;12(1):2208. doi: 10.1038/s41467-021-22458-9.
The B1 and B2 lineages of B cells contribute to protection from pathogens in distinct ways. The role of the DNA CpG methylome in specifying these two B-cell fates is still unclear. Here we profile the CpG modifications and transcriptomes of peritoneal B1a and follicular B2 cells, as well as their respective proB cell precursors in the fetal liver and adult bone marrow from wild-type and CD19-Cre Dnmt3a floxed mice lacking DNMT3A in the B lineage. We show that an underlying foundational CpG methylome is stably established during B lineage commitment and is overlaid with a DNMT3A-maintained dynamic methylome that is sculpted in distinct ways in B1a and B2 cells. This dynamic DNMT3A-maintained methylome is composed of novel enhancers that are closely linked to lineage-specific genes. While DNMT3A maintains the methylation state of these enhancers in both B1a and B2 cells, the dynamic methylome undergoes a prominent programmed demethylation event during B1a but not B2 cell development. We propose that the methylation pattern of DNMT3A-maintained enhancers is determined by the coincident recruitment of DNMT3A and TET enzymes, which regulate the developmental expression of B1a and B2 lineage-specific genes.
B 细胞的 B1 和 B2 谱系以不同的方式有助于抵御病原体。DNA CpG 甲基组在指定这两种 B 细胞命运中的作用尚不清楚。在这里，我们对来自野生型和 CD19-Cre Dnmt3a floxed 小鼠的胎儿肝脏和成年骨髓中的腹膜 B1a 和滤泡 B2 细胞以及它们各自的前 B 细胞进行了 CpG 修饰和转录组分析，这些小鼠在 B 谱系中缺乏 DNMT3A。我们表明，在 B 谱系分化过程中，会稳定建立一个基础的 CpG 甲基组，并且该甲基组会被 DNMT3A 维持的动态甲基组覆盖，该动态甲基组在 B1a 和 B2 细胞中以不同的方式进行修饰。这个动态的 DNMT3A 维持的甲基组由与谱系特异性基因密切相关的新型增强子组成。虽然 DNMT3A 在 B1a 和 B2 细胞中维持这些增强子的甲基化状态，但在 B1a 细胞而不是 B2 细胞发育过程中，动态甲基组会发生显著的程序性去甲基化事件。我们提出，DNMT3A 维持的增强子的甲基化模式是由 DNMT3A 和 TET 酶的同时募集决定的，DNMT3A 和 TET 酶调节 B1a 和 B2 谱系特异性基因的发育表达。
