title: Self-assembled FUS binds active chromatin and regulates gene transcription.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Fused in sarcoma (FUS) is a DNA/RNA binding protein and mutations in FUS cause a subset of familial ALS. Most ALS mutations are clustered in the C-terminal nuclear localization sequence of FUS and consequently lead to the accumulation of protein inclusions in the cytoplasm. It remains debatable whether loss of FUS normal function in the nucleus or gain of toxic function in the cytoplasm plays a more critical role in the ALS etiology. Moreover, the physiological function of FUS in the nucleus remains to be fully understood. In this study, we found that a significant portion of nuclear FUS was bound to active chromatin and that the ALS mutations dramatically decreased FUS chromatin binding ability. Functionally, the chromatin binding is required for FUS transcription activation, but not for alternative splicing regulation. The N-terminal QGSY (glutamine-glycine-serine-tyrosine)-rich region (amino acids 1-164) mediates FUS self-assembly in the nucleus of mammalian cells and the self-assembly is essential for its chromatin binding and transcription activation. In addition, RNA binding is also required for FUS self-assembly and chromatin binding. Together, our results suggest a functional assembly of FUS in the nucleus under physiological conditions, which is different from the cytoplasmic inclusions. The ALS mutations can cause loss of function in the nucleus by disrupting this assembly and chromatin binding.
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536.
authors.forename: Liuqing
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Gal
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536 haining@uky.edu.
authors.forename: Haining
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D015153:Blotting, Western; D002843:Chromatin / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*
chemical_list: D002843:Chromatin; D034702:RNA-Binding Protein FUS
keywords: amyotrophic lateral sclerosis; chromatin binding; fused in sarcoma; self-assembly; transcription