Epigenetic programming underpins B cell dysfunction in human SLE
Epigenetic programming underpins B cell dysfunction in human SLE
复制标题
DOI：
10.1038/s41590-019-0419-9
复制
发表时间：
2019-08-01
影响因子：
30.5
通讯作者：
Boss, Jeremy M.
中科院分区：
文献类型：
--
作者：
Scharer, Christopher D.;Blalock, Emily L.;Boss, Jeremy M.
系统性红斑狼疮 (SLE) 的特征是源自新激活的幼稚细胞的滤泡外致病性 B 细胞的扩增。尽管这些细胞表达不同的标记，但它们的表观遗传结构以及它如何促进系统性红斑狼疮仍然知之甚少。为了解决这个问题，我们确定了来自 SLE 受试者和健康对照的五个人类 B 细胞亚群（包括新定义的效应 B 细胞亚群）的 DNA 甲基化组、染色质可及性谱和转录组。我们的数据定义了子集的分化层次，并阐明了效应 B 细胞和记忆 B 细胞之间的表观遗传和转录差异。重要的是，SLE 分子特征已经在静息初始细胞中建立，并且主要是 AP-1 和 EGR 转录因子基序中可及染色质的富集。这些因素与 T-BET 协同作用，塑造了扩展的 SLE 效应 B 细胞亚群的表观基因组。因此，我们的数据定义了 SLE 致病性 B 细胞功能障碍的分子基础。
Systemic lupus erythematosus (SLE) is characterized by the expansion of extrafollicular pathogenic B cells derived from newly activated naive cells. Although these cells express distinct markers, their epigenetic architecture and how it contributes to SLE remain poorly understood. To address this, we determined the DNA methylomes, chromatin accessibility profiles and transcriptomes from five human B cell subsets, including a newly defined effector B cell subset, from subjects with SLE and healthy controls. Our data define a differentiation hierarchy for the subsets and elucidate the epigenetic and transcriptional differences between effector and memory B cells. Importantly, an SLE molecular signature was already established in resting naive cells and was dominated by enrichment of accessible chromatin in motifs for AP-1 and EGR transcription factors. Together, these factors acted in synergy with T-BET to shape the epigenome of expanded SLE effector B cell subsets. Thus, our data define the molecular foundation of pathogenic B cell dysfunction in SLE.