Journal Article

Self-assembled FUS binds active chromatin and regulates gene transcription

Zhu, Haining, Gal, Jozsef, Yang, Liuqing, Chen, Jing

2014

Overview

Significance Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and mutations in fused in sarcoma (FUS) cause a subset of familial ALS. Mutant FUS forms cytoplasmic inclusions, but it is unclear whether loss of FUS function in the nucleus or toxicity gained in the cytoplasm is more critical in the ALS etiology. The physiological function of FUS is also uncharacterized. We found that a significant portion of FUS was bound to active chromatin and that ALS mutations dramatically reduced FUS chromatin binding. A high order FUS assembly is mediated by the N-terminal QGSY (glutamine-glycine-serine-tyrosine)-rich region and is required for FUS chromatin binding and the transcription activation by FUS. ALS mutations in FUS can cause its loss of function in the nucleus by disrupting this assembly and chromatin binding. 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.

• Publisher: National Academy of Sciences
• Subject: Amino acids / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Binding sites / Biochemistry / Biological Sciences / Blotting, Western / Chromatin / Chromatin - metabolism / Cytoplasm / cytoplasmic inclusions / etiology / Gene Expression Regulation - genetics / Gene Expression Regulation - physiology / Genes / Genetic mutation / Humans / Inclusion Bodies - genetics / Inclusion Bodies - metabolism / mutants / Mutation / Mutation - genetics / Physiology / Proteins / Ribonucleic acid / RNA / RNA-Binding Protein FUS - genetics / RNA-Binding Protein FUS - metabolism / Sarcoma / Self assembly / Splicing / toxicity / transcription (genetics) / Transcription, Genetic - genetics / Transcription, Genetic - physiology / Transcriptional activation / Transcriptional regulatory elements