Nuclear role of WASp in the pathogenesis of dysregulated TH1 immunity in human Wiskott-Aldrich syndrome.
Nuclear role of WASp in the pathogenesis of dysregulated TH1 immunity in human Wiskott-Aldrich syndrome.
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DOI：
10.1126/scitranslmed.3000813
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发表时间：
2010-06-23
影响因子：
17.1
通讯作者：
Vyas YM
中科院分区：
文献类型：
--
作者：
Taylor MD;Sadhukhan S;Kottangada P;Ramgopal A;Sarkar K;D'Silva S;Selvakumar A;Candotti F;Vyas YM
X连锁Wiskott-Aldrich综合征（WAS）是一种由WAS蛋白（WASp）缺乏引起的联合免疫缺陷和自身免疫性疾病，其临床病理学反映了受损的辅助性T细胞1（TH 1）免疫与完整的TH 2免疫的潜在共存。这表明WASp在TH亚型免疫模式中的作用，但人类WAS中TH 1-TH 2失衡的分子基础尚不清楚。我们已经发现了核作用WASp在转录调节TH 1调节基因TBX 21在染色质水平。在原代TH 1分化细胞中，在细胞核中发现一部分WASp，在那里它被募集到TBX 21基因的近端启动子基因座，但不募集到GATA 3（TH 2调节基因）或RORc（TH 17调节基因）的核心启动子。全基因组定位表明WASp在体内与基因调控网络的关联，该基因调控网络在人类TH细胞基因组中协调TH 1细胞命运选择。在功能上，核WASp与H3 K4三甲基转移酶[RBBP 5（视网膜母细胞瘤结合蛋白5）]和H3 K9/H3 K36三去甲基酶[JMJD 2A（含Jumonji结构域的蛋白2A）]蛋白相关，并且它们在体外和体内的酶活性是在原代分化的TH 1细胞中在TBX 21近端启动子处实现转录允许的染色质动力学所必需的。在TH 1分化过程中，WASp的丢失伴随RBBP 5富集的减少，在WAS患者的一个子集中，TBX 21近端启动子位点的丝状肌动蛋白也是如此。因此，当在TH 1分化条件下驱动时，来自自然突变或RNA干扰介导的耗竭的人WASP缺陷型TH细胞表现出抑制的TBX 21启动子动力学。这些染色质紊乱伴随T-BET信使RNA和蛋白质表达缺陷以及TH 1功能受损，这些缺陷通过重新引入WASp而得到改善。我们的研究结果揭示了WASp在T-BET转录的表观遗传控制中的一个先前未被认识的作用，并通过将TBX 21启动子处的异常组蛋白甲基化与失调的适应性免疫联系起来，为WAS的发病机制提供了一种新的机制。
The clinical symptomatology in the X-linked Wiskott-Aldrich syndrome (WAS), a combined immunodeficiency and autoimmune disease resulting from WAS protein (WASp) deficiency, reflects the underlying coexistence of an impaired T helper 1 (TH1) immunity alongside intact TH2 immunity. This suggests a role for WASp in patterning TH subtype immunity, yet the molecular basis for the TH1-TH2 imbalance in human WAS is unknown. We have discovered a nuclear role for WASp in the transcriptional regulation of the TH1 regulator gene TBX21 at the chromatin level. In primary TH1-differentiating cells, a fraction of WASp is found in the nucleus, where it is recruited to the proximal promoter locus of the TBX21 gene, but not to the core promoter of GATA3 (a TH2 regulator gene) or RORc (a TH17 regulator gene). Genome-wide mapping demonstrates association of WASp in vivo with the gene-regulatory network that orchestrates TH1 cell fate choice in the human TH cell genome. Functionally, nuclear WASp associates with H3K4 trimethyltransferase [RBBP5 (retinoblastoma-binding protein 5)] and H3K9/H3K36 tridemethylase [JMJD2A (Jumonji domain-containing protein 2A)] proteins, and their enzymatic activity in vitro and in vivo is required for achieving transcription-permissive chromatin dynamics at the TBX21 proximal promoter in primary differentiating TH1 cells. During TH1 differentiation, the loss of WASp accompanies decreased enrichment of RBBP5 and, in a subset of WAS patients, also of filamentous actin at the TBX21 proximal promoter locus. Accordingly, human WASp-deficient TH cells, from natural mutation or RNA interference–mediated depletion, demonstrate repressed TBX21 promoter dynamics when driven under TH1-differentiating conditions. These chromatin derangements accompany deficient T-BET messenger RNA and protein expression and impaired TH1 function, defects that are ameliorated by reintroducing WASp. Our findings reveal a previously unappreciated role of WASp in the epigenetic control of T-BET transcription and provide a new mechanism for the pathogenesis of WAS by linking aberrant histone methylation at the TBX21 promoter to dysregulated adaptive immunity.
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影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
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Ren, Bing
影响因子：
14.8
作者：
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通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
14.9
作者：
Ji X;Li W;Song J;Wei L;Liu XS
通讯作者：
Liu XS
影响因子：
32.4
作者：
Lee, GR;Fields, PE;Flavell, RA
通讯作者：
Flavell, RA