R-loops cause genomic instability in T helper lymphocytes from patients with Wiskott-Aldrich syndrome.
R-loops cause genomic instability in T helper lymphocytes from patients with Wiskott-Aldrich syndrome.
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R环引起Wiskott-Aldrich综合征患者的T辅助淋巴细胞的基因组不稳定性。
DOI：
10.1016/j.jaci.2017.11.023
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Vyas YM
中科院分区：
文献类型：
--
作者：
Sarkar K;Han SS;Wen KK;Ochs HD;Dupré L;Seidman MM;Vyas YM
Wiskott-Aldrich综合征(Wiskott-Aldrich综合征)、X连锁血小板减少症(XLT)和X连锁中性粒细胞减少症(XLN)是由影响黄蜂表达或活性的IS突变引起的，表现为免疫缺陷、自身免疫、基因组不稳定和淋巴样癌。黄蜂支持细胞质中丝状肌动蛋白的形成和细胞核中的基因转录。虽然XLT/WAS的遗传基础已被阐明，但黄蜂突变形式与这些疾病的不同特征之间的关系仍不明确。为了明确XLT/AS临床谱系中Th细胞缺陷和基因组不稳定的程度与基因转录功能障碍之间的因果关系。在人Th1或Th2偏斜细胞培养系统中，共转录R环(RNA：DNA双链和移位单链DNA)和DNA双链断裂(DSB)在多个XLT和患者样本中被监测，在去黄蜂的正常T细胞中被监测。与Th2-细胞相比，黄蜂缺乏引起Th1-细胞中R-环和R-环介导的DSB增加。机制上，Th1细胞中丝氨酸2非磷酸化RNA聚合酶II的染色质占有率增加，而R环阻止因子拓扑异构酶1的染色质占有率在IFNG和Tbx21的R环富集区减少。这些异常伴随着IFNG和Tbx21的未剪接(内含子保留)增加和剪接的mRNA减少，但不包括IL13(Th2基因)。值得注意的是，R环和DSB的细胞负荷增加，在RNaseH1介导的异位R环抑制后归一化，与疾病严重程度评分呈负相关。转录R环失衡是Th1免疫缺陷和基因不稳定性的一种新的分子病因。这项研究建议，细胞R环负荷可以作为XLT-IS临床谱中监测症状严重程度和预后的潜在生物标记物，并可以作为治疗的靶向。
Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN), caused by WAS mutations affecting WASp expression or activity, manifest in immunodeficiency, autoimmunity, genomic-instability, and lymphoid-cancer. WASp supports filamentous-actin formation in the cytoplasm and gene-transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined. To define how dysfunctional gene transcription is causally linked to the degree of Thelper (Th) cell deficiency and genomic instability in XLT/WAS clinical spectrum. In human Th1- or Th2-skewing cell culture systems, co-transcriptional R-loops (RNA:DNA duplex and displaced single-stranded DNA) and DNA double-strand breaks (DSBs) were monitored in multiple XLT and WAS patient samples, and in normal T cells depleted of WASp. WASp-deficiency provokes increased R-loops and R-loop-mediated DSBs in Th1-cells relative to Th2-cells. Mechanistically, chromatin-occupancy of Serine2-unphosphorylated-RNA Polymerase II is increased and that of topoisomerase-1, a R-loop preventing factor, is decreased at R-loop-enriched regions of IFNG and TBX21 (Th1 genes) in Th1-cells. These aberrations accompany increased unspliced (intron-retained) and decreased spliced mRNA of IFNG and TBX21 but not of IL13 (Th2-gene). Significantly, increased cellular load of R-loops and DSBs, which are normalized upon RNaseH1-mediated suppression of ectopic R-loops, inversely correlates with disease severity scores. Transcriptional R-loop imbalance is a novel molecular defect etiologic in Th1-immunodeficiency and genomic-instability in WAS. The study proposes that cellular R-loop load could be used as a potential biomarker for monitoring symptom severity and prognostic outcome in the XLT-WAS clinical spectrum, and could be targeted therapeutically.
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DOI：
10.1016/j.tig.2016.10.002
发表时间：
2016-12
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Chédin F
通讯作者：
Chédin F
影响因子：
16.8
作者：
Chen PB;Chen HV;Acharya D;Rando OJ;Fazzio TG
通讯作者：
Fazzio TG
影响因子：
16
作者：
Hatchi, Elodie;Skourti-Stathaki, Konstantina;Ventz, Steffen;Pinello, Luca;Yen, Angela;Kamieniarz-Gdula, Kinga;Dimitrov, Stoil;Pathania, Shailja;McKinney, Kristine M.;Eaton, Matthew L.;Kellis, Manolis;Hill, Sarah J.;Parmigiani, Giovanni;Proudfoot, Nicholas J.;Livingston, David M.
通讯作者：
Livingston, David M.
R环的形成是未甲基化的人类CpG岛启动子的独特特征。
影响因子：
16
作者：
Ginno PA;Lott PL;Christensen HC;Korf I;Chédin F
通讯作者：
Chédin F
影响因子：
10.5
作者：
Herrera-Moyano E;Mergui X;García-Rubio ML;Barroso S;Aguilera A
通讯作者：
Aguilera A