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抑制发育转录因子网络触发了人类质前代细胞中与衰老相关的基因表达

John N Mariani¹, Benjamin Mansky², Pernille M Madsen^2,3

¹Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA. John_mariani@urmc.rochester.edu.

Nature communications

|May 8, 2024

概括

衰老会降低人类质原生细胞 (hGPCs) 繁殖的能力. 形成一个抑制MYC的环境,阻碍质细胞扩张,促进衰老.

科学领域:

神经科学是一个神经科学.
细胞生物学细胞生物学
发展生物学发展生物学

背景情况:

人类质原生细胞 (hGPCs) 随着年龄的增长和脱髓化后失去扩张的能力.
了解基质衰老背后的分子机制对于再生医学至关重要.

研究的目的:

为了研究与衰老相关的转录和表观遗传变化,在人类的质前代细胞.
确定有助于老化hGPCs增殖能力下降的关键监管因素.

主要方法:

用RNA测序来比较胎儿和成人hGPCs的基因表达特征.
进行了微RNA (miRNA) 分析,以确定与年龄相关的miRNA特征.
对特定转录因子的过度表达研究在诱导多能干细胞 (iPSC) 衍生的hGPC中进行.

主要成果:

确定了与年龄相关的转录性变化,包括对线粒体扩张和与衰老相关程序激活至关重要的基因的抑制.
一个涉及MYC,ZNF274,MAX,IKZF3和E2F6的抑制转录因子网络被发现是成人hGPCs的核心.
这些因子在iPSC衍生的hGPC中过度表达诱导了线粒老化和抑制了增殖基因表达.
一个成年人选择性的miRNA签名出现了,进一步限制了老年GPCs的扩展能力.

结论:

质老化涉及MYC抑制环境的获得,这限制了质扩张.
鉴定到的质扩张抑制剂可能是治疗目标,用于使老年hGPCs复原.
针对这些与年龄相关的分子变化,可以恢复质前代细胞的增殖潜力.

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