Hydroxycarbamide effects on DNA methylation and gene expression in myeloproliferative neoplasms.
Hydroxycarbamide effects on DNA methylation and gene expression in myeloproliferative neoplasms.
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DOI：
10.1101/gr.270066.120
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发表时间：
2021-08
期刊：
影响因子：
7
通讯作者：
Oakey RJ
中科院分区：
文献类型：
--
作者：
Contreras Castillo S;Montibus B;Rocha A;Duke W;von Meyenn F;McLornan D;Harrison C;Mullally A;Schulz R;Oakey RJ
羟基脲（HC，hydroxyurea）是一种诱导细胞周期阻滞的细胞减灭药物。然而，新的证据表明，HC通过转录因子的活性和DNA甲基化在转录调节中起作用。在骨髓增生性肿瘤（MPN）的背景下检查HC的全球作用机制，HC是一线治疗，将更好地了解其分子效应。为了探索HC全基因组的影响，在小鼠MPN模型中对用HC处理的处于不同分化阶段的两种临床相关细胞类型进行转录组学分析。这项研究是在MPN患者中重复的，通过分析全基因组基因表达和DNA甲基化，使用纵向收集的患者血液样本，在HC暴露之前和之后。HC对转录组的影响不仅与细胞周期中断有关，而且与造血功能有关。此外，药物治疗后，一组基因在小鼠造血干细胞（HSC）中恢复到正常表达水平，包括造血的主要调节因子RUNX1。在人类中，HC显着修改DNA甲基化水平在几个远端调控区，我们表明，这是与SPI1结合位点和SPI1基因座本身的HSC。我们已经确定了新的目标HC，包括关键的转录因子参与造血，并首次报告异常甲基化模式在MPN患者的主调节基因SPI1及其远端结合位点，HC是能够恢复到正常水平。
Hydroxycarbamide (HC, hydroxyurea) is a cytoreductive drug inducing cell cycle blockade. However, emerging evidence suggests that HC plays a role in the modulation of transcription through the activity of transcription factors and DNA methylation. Examining the global mechanism of action of HC in the context of myeloproliferative neoplasms (MPNs), for which HC is the first-line treatment, will provide a better understanding of its molecular effects. To explore the effects of HC genome-wide, transcriptomic analyses were performed on two clinically relevant cell types at different stages of differentiation treated with HC in a murine MPN model. This study was replicated in MPN patients by profiling genome-wide gene expression and DNA methylation using patient blood samples collected longitudinally, before and following HC exposure. The effects of HC on the transcriptome were not only associated with cell cycle interruption but also with hematopoietic functions. Moreover, a group of genes were restored to normal expression levels in murine hematopoietic stem cells (HSCs) following drug treatment, including the master regulator of hematopoiesis, RUNX1. In humans, HC significantly modifies DNA methylation levels in HSCs at several distal regulatory regions, which we show to be associated with SPI1 binding sites and at the SPI1 locus itself. We have identified novel targets of HC that include pivotal transcription factors involved in hematopoiesis, and for the first time we report abnormal methylation patterns in MPN patients at the master regulator gene SPI1 and its distal binding sites, which HC is able to restore to normal levels.
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影响因子：
7
作者：
Hinoue, Toshinori;Weisenberger, Daniel J.;Laird, Peter W.
通讯作者：
Laird, Peter W.
DOI：
10.1007/978-1-4899-7708-3_5
发表时间：
2017-01-01
期刊：
PLANT EPIGENETICS: METHODS AND PROTOCOLS, 2ND EDITION
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作者：
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Weber, Michael