Duncan Christopher G, Kondilis-Mangum Hrisavgi D, Grimm Sara A, Bushel Pierre R, Chrysovergis Kaliopi, Roberts John D, Tyson Frederick L, Merrick B Alex, Wade Paul A
Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
G3 (Bethesda). 2018 Mar 2;8(3):805-813. doi: 10.1534/g3.117.300446.
The DNA methyltransferase, , is dynamically regulated throughout mammalian B cell development and upon activation by antigenic stimulation. inactivation in hematopoietic stem cells has been shown to drive B cell-related malignancies, including chronic lymphocytic leukemia, and associates with specific DNA methylation patterns in transformed cells. However, while it is clear that inactivation of in hematopoietic stem cells has profound functional effects, the consequences of inactivation in cells of the B lineage are unclear. To assess whether loss of at the earliest stages of B cell development lead to DNA methylation defects that might impair function, we selectively inactivated early in mouse B cell development and then utilized whole genome bisulfite sequencing to generate base-resolution profiles of and naïve splenic B cells. Overall, we find that global methylation patterns are largely consistent between and naïve B cells, indicating a minimal functional effect of DNMT3A in mature B cells. However, loss of induced 449 focal DNA methylation changes, dominated by loss-of-methylation events. Regions found to be hypomethylated in naïve splenic B cells were enriched in gene bodies of transcripts expressed in B cells, a fraction of which are implicated in B cell-related disease. Overall, the results from this study suggest that factors other than are the major drivers for methylome maintenance in B cell development.
DNA甲基转移酶 在整个哺乳动物B细胞发育过程以及抗原刺激激活后均受到动态调节。造血干细胞中的 失活已被证明会引发包括慢性淋巴细胞白血病在内的B细胞相关恶性肿瘤，并与转化细胞中的特定DNA甲基化模式相关。然而，虽然很明显造血干细胞中的 失活具有深远的功能影响，但B系细胞中 失活的后果尚不清楚。为了评估B细胞发育最早阶段的 缺失是否会导致可能损害功能的DNA甲基化缺陷，我们在小鼠B细胞发育早期选择性地使 失活，然后利用全基因组亚硫酸氢盐测序来生成 和 幼稚脾B细胞的碱基分辨率图谱。总体而言，我们发现 和 幼稚B细胞之间的整体甲基化模式在很大程度上是一致的，这表明DNMT3A在成熟B细胞中的功能影响最小。然而， 的缺失诱导了449个局部DNA甲基化变化，主要是甲基化缺失事件。在 幼稚脾B细胞中发现低甲基化的区域富含B细胞中表达的转录本的基因体，其中一部分与B细胞相关疾病有关。总体而言，这项研究的结果表明，除 之外的其他因素是B细胞发育中甲基化组维持的主要驱动因素。
