新生染色体结构的变化调节了器官纤维化中亲纤维转录组和肌纤维细胞出现的激活
Morgan D Basta1, Svetlana Petruk2, Ross Summer3
1Department of Pathology and Genomic Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
iScience
|May 30, 2023
概括
UTX/KDM6B酶延迟了染色质凝聚,使肌纤维细胞激活和纤维化成为可能. 抑制UTX/KDM6B阻断了这一过程,在临床前模型中预防了纤维化.
科学领域:
- 表观遗传学和分子生物学
- 细胞生物学 细胞生物学
- 纤维化研究 纤维化研究
背景情况:
- 纤维化涉及细胞重新编程到肌纤维细胞,导致病态的细胞外矩阵积累.
- 由H3K27me3标记的缩色素结构通常抑制参与肌纤维细胞激活的基因.
研究的目的:
- 研究染色体结构的修改,特别是H3K27me3,如何调节肌纤维细胞分化过程中的基因激活.
- 确定控制染色体脱凝和亲纤维基因表达的关键分子参与者.
主要方法:
- 研究了H3K27me3脱甲基酶UTX/KDM6B在肌纤维细胞前体细胞分化中的作用.
- 利用透镜和肺纤维化模型来评估UTX/KDM6B抑制的影响.
- 分析了染色体结构,转录因子结合 (MRTF-A) 和基因表达模式.
主要成果:
- UTX/KDM6B活动通过延迟H3K27me3在新生DNA上的积累,创造了脱凝染色素的窗口.
- 这种脱凝状态有助于亲纤维转录因子MRTF-A与新生的DNA结合.
- 抑制UTX/KDM6B导致染色体凝聚,阻止MRTF-A结合,并阻断亲纤维基因激活,从而抑制纤维化.
结论:
- UTX/KDM6B是纤维化的关键调节者,通过控制染色质结构和亲纤维基因表达.
- 准UTX/KDM6B脱甲基酶活性是预防器官纤维化的潜在治疗策略.
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