红状腺系染色质可访问性地图有助于识别和验证NFIX作为胎儿血红蛋白抑制剂
Mudit Chaand1, Chris Fiore2, Brian Johnston2
1Syros Pharmaceuticals, Cambridge, MA, USA. mchaand@syros.com.
Communications biology
|June 14, 2023
概括
研究人员确定NFIX是抑制成人胎儿马球蛋白 (HBG) 的关键因素. 减少NFIX可以促进胎儿血红蛋白 (HbF) 产生,为血红蛋白病提供了一个新的治疗点.
科学领域:
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
- 血液学 血液学 血液学
背景情况:
- 人类遗传学支持重新激活胎儿马球蛋白 (HBG) 作为beta-hemoglobinopathies的治疗策略.
- 了解从HBG切换到成人β球蛋白 (HBB) 表达的过程对于开发有效的治疗方法至关重要.
研究的目的:
- 确定控制从胎儿玛球蛋白 (HBG) 转换为成人β球蛋白 (HBB) 表达的调节因素.
- 调查NFIX在抑制成年红状腺细胞HBG表达中的作用.
主要方法:
- 用高通量测序 (ATAC-seq) 进行转移酶可访问染色质的测试,对成年骨髓 (BM) 和胎儿带血 (CB) 红色细胞进行了测试.
- 在红状腺细胞中进行了NFIX敲击和过度表达实验.
- 分析HBG mRNA,胎儿血红蛋白 (HbF) 蛋白水平,染色质可访问性和DNA甲基化.
主要成果:
- 与胎儿细胞相比,ATAC-seq显示了NFI DNA结合动机的丰富,并增加了NFIX促进器在成年细胞中的可访问性.
- 在成年细胞中,NFIX knockdown导致HBG mRNA和HbF蛋白的增加,增强了染色质的可访问性和减少了HBG促进体的DNA甲基化.
- 胎儿细胞中的NFIX过度表达降低了HbF水平.
结论:
- 在成年红状腺细胞中,NFIX作为胎儿马球蛋白 (HBG) 表达的抑制剂.
- NFIX被确定为激活胎儿血红蛋白 (HbF) 的新疗法标.
- 针对NFIX的目标有望为开发新型血红蛋白病变治疗方法提供希望.
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