Bach1抑制剂HPP-D介导镰状红细胞祖细胞γ-珠蛋白基因活化

IF 2.1 4区 医学 Q3 HEMATOLOGY Blood Cells Molecules and Diseases Pub Date : 2023-08-17 DOI:10.1016/j.bcmd.2023.102792
Chithra D. Palani , Xingguo Zhu , Manickam Alagar , Otis C. Attucks , Betty S. Pace
{"title":"Bach1抑制剂HPP-D介导镰状红细胞祖细胞γ-珠蛋白基因活化","authors":"Chithra D. Palani ,&nbsp;Xingguo Zhu ,&nbsp;Manickam Alagar ,&nbsp;Otis C. Attucks ,&nbsp;Betty S. Pace","doi":"10.1016/j.bcmd.2023.102792","DOIUrl":null,"url":null,"abstract":"<div><p><span><span><span><span>Sickle cell disease (SCD) is the most common β-hemoglobinopathy caused by various mutations in the adult β-globin gene resulting in </span>sickle hemoglobin production, chronic </span>hemolytic anemia<span>, pain, and progressive organ damage. The best therapeutic strategies to manage the clinical symptoms of SCD is the induction of fetal hemoglobin (HbF) using chemical agents. At present, among the Food and Drug Administration-approved </span></span>drugs<span> to treat SCD, hydroxyurea<span><span> is the only one proven to induce HbF protein synthesis, however, it is not effective in all people. Therefore, we evaluated the ability of the novel Bach1 inhibitor, HPP-D to induce HbF in KU812 cells and primary sickle erythroid progenitors. HPP-D increased HbF and decreased Bach1 protein levels in both cell types. Furthermore, </span>chromatin immunoprecipitation assay<span> showed reduced Bach1 and increased NRF2 binding to the γ-globin promoter antioxidant response elements. We also observed increased levels of the active </span></span></span></span>histone<span> marks H3K4Me1 and H3K4Me3 supporting an open chromatin configuration. In primary sickle erythroid progenitors, HPP-D increased γ-globin transcription and HbF positive cells and reduced sickled erythroid progenitors under hypoxia conditions. Collectively, our data demonstrate that HPP-D induces γ-globin gene transcription through Bach1 inhibition and enhanced NRF2 binding in the γ-globin promoter antioxidant response elements.</span></p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"104 ","pages":"Article 102792"},"PeriodicalIF":2.1000,"publicationDate":"2023-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Bach1 inhibitor HPP-D mediates γ-globin gene activation in sickle erythroid progenitors\",\"authors\":\"Chithra D. Palani ,&nbsp;Xingguo Zhu ,&nbsp;Manickam Alagar ,&nbsp;Otis C. Attucks ,&nbsp;Betty S. Pace\",\"doi\":\"10.1016/j.bcmd.2023.102792\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p><span><span><span><span>Sickle cell disease (SCD) is the most common β-hemoglobinopathy caused by various mutations in the adult β-globin gene resulting in </span>sickle hemoglobin production, chronic </span>hemolytic anemia<span>, pain, and progressive organ damage. The best therapeutic strategies to manage the clinical symptoms of SCD is the induction of fetal hemoglobin (HbF) using chemical agents. At present, among the Food and Drug Administration-approved </span></span>drugs<span> to treat SCD, hydroxyurea<span><span> is the only one proven to induce HbF protein synthesis, however, it is not effective in all people. Therefore, we evaluated the ability of the novel Bach1 inhibitor, HPP-D to induce HbF in KU812 cells and primary sickle erythroid progenitors. HPP-D increased HbF and decreased Bach1 protein levels in both cell types. Furthermore, </span>chromatin immunoprecipitation assay<span> showed reduced Bach1 and increased NRF2 binding to the γ-globin promoter antioxidant response elements. We also observed increased levels of the active </span></span></span></span>histone<span> marks H3K4Me1 and H3K4Me3 supporting an open chromatin configuration. In primary sickle erythroid progenitors, HPP-D increased γ-globin transcription and HbF positive cells and reduced sickled erythroid progenitors under hypoxia conditions. Collectively, our data demonstrate that HPP-D induces γ-globin gene transcription through Bach1 inhibition and enhanced NRF2 binding in the γ-globin promoter antioxidant response elements.</span></p></div>\",\"PeriodicalId\":8972,\"journal\":{\"name\":\"Blood Cells Molecules and Diseases\",\"volume\":\"104 \",\"pages\":\"Article 102792\"},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2023-08-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Blood Cells Molecules and Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1079979623000694\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Cells Molecules and Diseases","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1079979623000694","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

镰状细胞病(SCD)是最常见的β-血红蛋白病,由成人β-珠蛋白基因的各种突变引起,导致镰状血红蛋白产生、慢性溶血性贫血、疼痛和进行性器官损伤。控制SCD临床症状的最佳治疗策略是使用化学制剂诱导胎儿血红蛋白(HbF)。目前,在美国食品药品监督管理局批准的治疗SCD的药物中,羟基脲是唯一一种被证明能诱导HbF蛋白合成的药物,但它并不是对所有人都有效。因此,我们评估了新型Bach1抑制剂HPP-D在KU812细胞和原代镰状红系祖细胞中诱导HbF的能力。HPP-D增加了两种细胞类型中的HbF并降低了Bach1蛋白水平。此外,染色质免疫沉淀分析显示,Bach1减少,NRF2与γ-珠蛋白启动子抗氧化反应元件的结合增加。我们还观察到活性组蛋白标记H3K4Me1和H3K4Me3的水平增加,支持开放染色质构型。在原代镰状红系祖细胞中,HPP-D增加了γ-珠蛋白转录和HbF阳性细胞,并在缺氧条件下减少了镰状红细胞祖细胞。总之,我们的数据表明,HPP-D通过抑制Bach1和增强γ-珠蛋白启动子抗氧化反应元件中NRF2的结合来诱导γ-珠蛋白质基因转录。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Bach1 inhibitor HPP-D mediates γ-globin gene activation in sickle erythroid progenitors

Sickle cell disease (SCD) is the most common β-hemoglobinopathy caused by various mutations in the adult β-globin gene resulting in sickle hemoglobin production, chronic hemolytic anemia, pain, and progressive organ damage. The best therapeutic strategies to manage the clinical symptoms of SCD is the induction of fetal hemoglobin (HbF) using chemical agents. At present, among the Food and Drug Administration-approved drugs to treat SCD, hydroxyurea is the only one proven to induce HbF protein synthesis, however, it is not effective in all people. Therefore, we evaluated the ability of the novel Bach1 inhibitor, HPP-D to induce HbF in KU812 cells and primary sickle erythroid progenitors. HPP-D increased HbF and decreased Bach1 protein levels in both cell types. Furthermore, chromatin immunoprecipitation assay showed reduced Bach1 and increased NRF2 binding to the γ-globin promoter antioxidant response elements. We also observed increased levels of the active histone marks H3K4Me1 and H3K4Me3 supporting an open chromatin configuration. In primary sickle erythroid progenitors, HPP-D increased γ-globin transcription and HbF positive cells and reduced sickled erythroid progenitors under hypoxia conditions. Collectively, our data demonstrate that HPP-D induces γ-globin gene transcription through Bach1 inhibition and enhanced NRF2 binding in the γ-globin promoter antioxidant response elements.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
4.90
自引率
0.00%
发文量
42
审稿时长
14 days
期刊介绍: Blood Cells, Molecules & Diseases emphasizes not only blood cells, but also covers the molecular basis of hematologic disease and studies of the diseases themselves. This is an invaluable resource to all those interested in the study of hematology, cell biology, immunology, and human genetics.
期刊最新文献
Editorial Board Corrigendum to “Clinical utility of relative telomere length analysis in pediatric bone marrow failure” [Blood Cells Mol. Dis. 109 (2024) 102882] Marked microcytosis and increased transferrin saturation: Think about variants in SLC11A2 (DMT1) Identification of Nfel1a and Nfel3 as novel regulators for zebrafish thrombopoiesis Hemophagocytic lymphohistiocytosis associated with immune checkpoint inhibitor use: A review of the current knowledge and future directions
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1