Cell-Cycle-Dependent Reconfiguration of the DNA Methylome during Terminal Differentiation of Human B Cells into Plasma Cells
Cell-Cycle-Dependent Reconfiguration of the DNA Methylome during Terminal Differentiation of Human B Cells into Plasma Cells
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DOI：
10.1016/j.celrep.2015.09.051
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发表时间：
2015-11-03
期刊：
影响因子：
8.8
通讯作者：
Fest, Thierry
中科院分区：
文献类型：
--
作者：
Caron, Gersende;Hussein, Mourad;Fest, Thierry
B细胞终末分化为浆细胞的分子机制是获得性免疫的主要决定因素，但仍然只有部分了解。在这里，我们提出的转录和表观基因组景观所产生的人类幼稚B细胞活化和分化成浆母细胞的细胞亚群。活化B细胞的细胞增殖与DNA甲基化水平的轻微降低有关，但随后是一个承诺步骤，其中S期同步分化开关与广泛的DNA去甲基化和增强子和浆细胞身份相关基因处5-羟甲基胞嘧啶的局部获得相关。TGF-β 1/SMAD 3信号转导和p53通路的下调支持了这一最后步骤，允许出现从B细胞向浆细胞过渡的CD 23阴性亚群。值得注意的是，PRDM 1（浆细胞命运所必需的基因）的羟甲基化与S期的进展相关联，揭示了细胞周期，DNA（羟基）甲基化和细胞命运决定之间的复杂联系。
Molecular mechanisms underlying terminal differentiation of B cells into plasma cells are major determinants of adaptive immunity but remain only partially understood. Here we present the transcriptional and epigenomic landscapes of cell subsets arising from activation of human naive B cells and differentiation into plasmablasts. Cell proliferation of activated B cells was linked to a slight decrease in DNA methylation levels, but followed by a committal step in which an S phase-synchronized differentiation switch was associated with an extensive DNA demethylation and local acquisition of 5-hydroxymethylcytosine at enhancers and genes related to plasma cell identity. Downregulation of both TGF-b1/SMAD3 signaling and p53 pathway supported this final step, allowing the emergence of a CD23-negative subpopulation in transition from B cells to plasma cells. Remarkably, hydroxymethylation of PRDM1, a gene essential for plasma cell fate, was coupled to progression in S phase, revealing an intricate connection among cell cycle, DNA (hydroxy) methylation, and cell fate determination.