Self-Assembled FUS Binds Active Chromatin and Regulates Gene Transcription


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.

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Published in Proceedings of the National Academy of Sciences of the United States of America, v. 111, no. 50, p. 17809-17814.

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This study was supported in part by the National Institutes of Neurological Disorder and Stroke Grant R01NS077284 and ALS Association Grant 6SE340 (to H.Z.). We acknowledge the University of Kentucky Proteomics Core, which is partially supported by the National Institute of General Medical Sciences COBRE Grant P20GM103486-09. The Orbitrap mass spectrometer was acquired by High-End Instrumentation Grant S10RR029127 (to H.Z.).