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在人类T细胞白血病病毒-1病原发生过程中CTCF结合部位的作用

Ancy Joseph¹, Xiaogang Cheng¹, John Harding¹

¹Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.

bioRxiv : the preprint server for biology

|June 10, 2024

概括

在HTLV-1中,CCCCTC结合蛋白结合部位 (vCTCF-BS) 调节了人性化小鼠的病毒感染和疾病进展. 破坏vCTCF-BS会减少病毒载量和T细胞激活,影响HTLV-1的致病性.

科学领域:

病毒学病毒学
免疫学免疫学免疫学
分子生物学分子生物学

背景情况:

人类T淋巴细胞病毒1型 (HTLV-1) 作为前病毒集成到宿主DNA中.
一个CCCCTC结合蛋白 (CTCF) 结合位点 (vCTCF-BS) 在前病毒中作为绝缘体,影响染色质结构和病毒基因表达.
以前的研究强调了vCTCF-BS在维护染色质结构,调节病毒表达和调节DNA和基因素甲基化中的作用.

研究的目的:

为了研究vCTCF-BS在HTLV-1感染和成人T细胞白血病/淋巴瘤 (ATL) 发病过程中的作用,在一个人性化的 (Hu) 鼠标模型中.
为了确定vCTCF-BS突变如何影响病毒载量,致病性和T淋巴细胞的活体反应.

主要方法:

用于胡鼠感染的三种细胞系:HTLV-1-WT (完整的前病毒),HTLV-1-CTCF (突变的vCTCF-BS) 和HTLV-1-p12stop (完整的vCTCF-BS与p12停止编码子).
感染了mitomycin治疗或辐射的HTLV-1生产细胞系的Hu小鼠.
评估了病原性,前病毒载荷 (PVL),脏重量,CD4 T细胞计数,并对胞进行了scRNAseq分析.

主要成果:

与HTLV-1-p12stop和HTLV-1-WT相比,HTLV-1-CTCF的感染显示出延迟的致病性.
受HTLV-1-CTCF感染的小鼠的PVL,脏重量和CD4 T细胞数量显著降低.
在感染HTLV-1-CTCF的小鼠中观察到PVL和死亡率之间的直接相关性.
在实验室中,vCTCF-BS被发现以时间依赖的方式调节税务表达.
scRNAseq数据表明,vCTCF-BS对于T淋巴细胞活化和扩张在体内至关重要.

结论:

该vCTCF-BS在调节HTLV-1税表达,前病毒载量和总体致病性在体内发挥着重要作用.
针对vCTCF-BS可能是管理HTLV-1感染和相关疾病 (如ATL) 的潜在策略.

关键词:

ATL ATL 在线播放在CTCF中,CTCF是指CTCF.基因甲基化 DNA 甲基化表观基因组是一个表观基因组.这就是HTLV.

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