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通过强制性染色体循环,重新激活发育性沉默的全球蛋白基因
Wulan Deng1, Jeremy W Rupon2, Ivan Krivega3
1Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Transcription Imaging Consortium, Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
Cell
|August 16, 2014
概括
强迫色素循环可以重新激活沉默的胚胎球蛋白基因,并促进成年细胞中的胎儿球蛋白生产. 这表明了控制全球蛋白基因转录的新疗法策略.
科学领域:
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
- 发育生物学 发展生物学
背景情况:
- 远端增强剂通过染色质循环调节基因转录.
- 位置控制区域 (LCR) 在发育过程中与红色素细胞中的β型全球蛋白基因相互作用.
- 之前的研究表明,使用人工手指诱导LCR促进器循环.
研究的目的:
- 为了调查是否强迫色素循环可以重新激活沉默的环球蛋白基因.
- 探索操纵LCR促进体相互作用的潜力,以达到治疗目的.
主要方法:
- 针对Ldb1自我关联域 (SA) 来对小鼠红细胞中沉默的胚胎球蛋白促进体进行向.
- 将SA向人类红红细胞中的胎儿γ-环球蛋白促进体.
- 评估全球蛋白基因转录和LCR促进体接触.
主要成果:
- 向SA在成年小鼠红细胞中重新激活了一个沉默的胚胎球蛋白基因,依赖于LCR.
- 在人体红细胞中,将SA向γ-环球蛋白促进体增加了γ-环球蛋白-LCR接触.
- 这导致γ-环球蛋白占总β-环球蛋白合成的~85%,减少了成年β-环球蛋白的表达.
结论:
- 强制色素循环可以克服发育基因沉默程序.
- 准LCR促进体相互作用为调节球蛋白基因表达提供了一种新的策略.
- 这种方法有可能在血红蛋白病变中进行治疗应用.
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