이헌구 (Mass General Hospital / Harvard Medical School) | 한빛사논문 > 한빛사

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Mass General Hospital / Harvard Medical School

Cell, 19 May 2023 | https://doi.org/10.1016/j.cell.2023.04.035 Site-specific R-loops induce CGG repeat contraction and fragile X gene reactivation

Hun-Goo Lee ^{1 2}, Sachiko Imaichi ^{1 2}, Elizabeth Kraeutler ^{1 2}, Rodrigo Aguilar ^{1 2}, Yong-Woo Lee ^{1 2}, Steven D. Sheridan ^{3 4}, Jeannie T. Lee ^{1 2 5}

¹Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
²Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
³Center for Quantitative Health Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
⁴Department of Psychiatry, Harvard Medical School, Boston, MA 02114, USA
⁵Lead contact: correspondence to Jeannie T. Lee

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 spectrum disorders, FXS results from epigenetic silencing of FMR1 due to a congenital trinucleotide (CGG) repeat expansion. By investigating conditions favorable to FMR1 reactivation, we find MEK and BRAF inhibitors that induce a strong repeat contraction and full FMR1 reactivation in cellular models. We trace the mechanism to DNA demethylation and site-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 DNA repair mechanisms that then drive excision of the long CGG repeat. Repeat contraction is specific to FMR1 and restores the production of FMRP protein. Our study therefore identifies a potential method of treating FXS in the future.

논문정보

형식Research article
게재일2023년 05월 (BRIC 등록일 2023-05-26)
연구진국외 연구진
분야 생명과학 > 신경생물학

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