Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression
Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression
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DOI：
10.1016/j.molimm.2016.07.015
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发表时间：
2016-09-01
影响因子：
3.6
通讯作者：
Hurwitz, Julia L.
中科院分区：
文献类型：
--
作者：
Jones, Bart G.;Penkert, Rhiannon R.;Hurwitz, Julia L.
女性和男性的抗体同种型表达模式以及对外源和自身抗原的免疫反应不同。例如，系统性红斑狼疮是一种与同种型偏向抗自身抗体的产生相关的病症，并且表现出 9:1 的女性：男性疾病比例。为了解释男性和女性 B 细胞反应之间的差异，我们试图确定雌激素受体 (ER) 与免疫球蛋白重链位点的直接相互作用。我们之前在重链开关 (S) 区域中发现的雌激素反应元件 (ERE) 鼓励了这一努力。我们使用来自 LPS 激活的 B 细胞的 DNA 和 ER α 特异性抗体进行了全基因组染色质免疫沉淀分析 (ChIP-seq)。结果显示 ER 与 DNA 的较宽区域结合，跨越从 J(H) 簇到 CB 的序列，峰值位于 E mu 和 S mu。网站。 ER α 结合的其他峰与重链基因座 3' 调控区 (3'RR) 中的 hs1,2 和 hs4 位点一致。 ER 与免疫球蛋白位点中关键调控元件直接结合的首次证明支持了我们的假设，即雌激素和其他核激素受体和配体可能直接影响抗体表达和类别转换重组 (CSR)。我们的假设鼓励进行新的实验来评估 ER 结合的后果。更好地了解免疫球蛋白重链位点中的 ER:DNA 相互作用以及各自的机制，最终可能会转化为更好地控制抗体表达、更好地防御病原体以及预防自身免疫性疾病引起的病理。 (C) 2016 Elsevier Ltd. 保留所有权利。
Females and males differ in antibody isotype expression patterns and in immune responses to foreign and self-antigens. For example, systemic lupus erythematosus is a condition that associates with the production of isotype-skewed anti-self antibodies, and exhibits a 9:1 female:male disease ratio. To explain differences between B cell responses in males and females, we sought to identify direct interactions of the estrogen receptor (ER) with the immunoglobulin heavy chain locus. This effort was encouraged by our previous identification of estrogen response elements (ERE) in heavy chain switch (S) regions. We conducted a full-genome chromatin immunoprecipitation analysis (ChIP-seq) using DNA from LPS-activated B cells and an ER alpha-specific antibody. Results revealed ER binding to a wide region of DNA, spanning sequences from the J(H) cluster to CB, with peaks in E mu and S mu. sites. Additional peaks of ER alpha binding were coincident with hs1,2 and hs4 sites in the 3' regulatory region (3'RR) of the heavy chain locus. This first demonstration of direct binding of ER to key regulatory elements in the immunoglobulin locus supports our hypothesis that estrogen and other nuclear hormone receptors and ligands may directly influence antibody expression and class switch recombination (CSR). Our hypothesis encourages the conduct of new experiments to evaluate the consequences of ER binding. A better understanding of ER:DNA interactions in the immunoglobulin heavy chain locus, and respective mechanisms, may ultimately translate to better control of antibody expression, better protection against pathogens, and prevention of pathologies caused by auto-immune disease. (C) 2016 Elsevier Ltd. All rights reserved.