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FUS liên quan đến thoái hóa thần kinh là một bộ điều chỉnh mới của sự biểu hiện gene theo nhịp sinh học
Tóm tắt
Các nhịp sinh học là những thay đổi sinh lý và hành vi dao động được điều khiển bởi một đồng hồ phân tử nội bộ, và sự rối loạn trong các nhịp sinh học đã được liên kết với quá trình lão hóa và nhiều bệnh thoái hóa thần kinh khác nhau. Tuy nhiên, bằng chứng trực tiếp kết nối các protein liên quan đến thoái hóa thần kinh với kiểm soát nhịp sinh học ở cấp độ phân tử vẫn còn thưa thớt. Sử dụng phân tích tổng hợp, động vật đồng bộ và dòng tế bào, tế bào và mô từ chuột knock-in FUS R521C, chúng tôi đã nghiên cứu vai trò của FUS trong việc điều chỉnh sự biểu hiện gene theo nhịp sinh học. Chúng tôi phát hiện ra rằng FUS, một protein hạt nhân có biểu hiện dao động được liên kết với bệnh sinh của bệnh teo cơ bên (ALS) và chứng mất trí trán-thái dương (FTD), đã tạo ra một con đường phản hồi mới để điều chỉnh sự biểu hiện gene theo nhịp sinh học. Protein nhịp sinh học cốt lõi REV-ERBα do gene Nr1d1 mã hóa gắn vào trình tự promoter của Fus và điều chỉnh sự biểu hiện của Fus. Trong khi đó, FUS nằm trong cùng một phức hợp với PER/CRY và ức chế sự biểu hiện của các gene nhịp sinh học cốt lõi chứa E box, chẳng hạn như Per2, bằng cách điều hòa sự chiếm lĩnh trình tự promoter của PSF-HDAC1. Đáng chú ý, một đột biến gây bệnh phổ biến của FUS (R521C) cho thấy liên kết tăng cường với PSF và gây giảm sự biểu hiện của Per2. Do đó, chúng tôi đã chứng minh rằng FUS là một chất điều chế sự biểu hiện gene theo nhịp sinh học, và cung cấp những hiểu biết cơ chế mới về sự ảnh hưởng lẫn nhau giữa kiểm soát nhịp sinh học và các protein liên quan đến thoái hóa thần kinh.
Từ khóa
#nhịp sinh học #thoái hóa thần kinh #FUS #protein #kiểm soát geneTài liệu tham khảo
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