美国马萨诸塞州综合医院Jeannie T. Lee小组发现，特定位点的R环诱导CGG重复收缩和脆弱的X基因重新激活。这一研究成果于2023年5月19日在线发表在国际学术期刊《细胞》上。

研究人员描述了一种通过招募内源性修复机制来纠正脆性X综合征（FXS）基因缺陷的方法。作为自闭症谱系障碍的主要原因，FXS是由于先天性三核苷酸（CGG）重复扩增导致FMR1的表观遗传沉默。通过研究有利于FMR1重新激活的条件，研究人员发现MEK和BRAF抑制剂能在细胞模型中诱导强烈的重复收缩和FMR1完全重新激活。研究人员将这一机制追溯到DNA去甲基化和特定位置的R环，这是重复收缩的必要和充分条件。

由去甲基化、新的FMR1转录和R环的形成组成的正反馈循环导致了内源性DNA修复机制的招募，然后驱动长CGG重复的切除。重复收缩对FMR1是特异性的，并恢复了FMRP蛋白的生产。因此，这项研究确定了未来治疗FXS的一种潜在方法。

附：英文原文

Title: Site-specific R-loops induce CGG repeat contraction and fragile X gene reactivation

Author: Hun-Goo Lee, Sachiko Imaichi, Elizabeth Kraeutler, Rodrigo Aguilar, Yong-Woo Lee, Steven D. Sheridan, Jeannie T. Lee

Issue&Volume: 2023-05-19

Abstract: Here, we describe an approach to correct the genetic defect in fragile X syndrome(FXS) via recruitment of endogenous repair mechanisms. A leading cause of autism spectrumdisorders, FXS results from epigenetic silencing of FMR1 due to a congenital trinucleotide (CGG) repeat expansion. By investigating conditionsfavorable to FMR1 reactivation, we find MEK and BRAF inhibitors that induce a strong repeat contractionand full FMR1 reactivation in cellular models. We trace the mechanism to DNA demethylation andsite-specific R-loops, which are necessary and sufficient for repeat contraction.A positive feedback cycle comprising demethylation, de novo FMR1 transcription, and R-loop formation results in the recruitment of endogenous DNArepair mechanisms that then drive excision of the long CGG repeat. Repeat contractionis specific to FMR1 and restores the production of FMRP protein. Our study therefore identifies a potentialmethod of treating FXS in the future.

DOI: 10.1016/j.cell.2023.04.035

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00469-5