Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription

Wang, Xiangting; Arai, Setsuo; Song, Xiaoyuan; Reichart, Donna; Du, Kun; Pascual, Gabriel; Tempst, Paul; Rosenfeld, Michael G.; Glass, Christopher K.; Kurokawa, Riki

doi:10.1038/nature06992

Cited by 902 publications

(863 citation statements)

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“…[6][7][8][9] FUS is a nucleoprotein that functions in DNA and RNA metabolism. 10 In this study, we found a large Japanese FALS family with mutations in the FUS gene with the characteristics of early onset. In addition, we report four mutations of the FUS gene in Japanese FALS.…”

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confidence: 83%

FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion

et al. 2010

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Mutations in the fused in sarcoma (FUS, also known as translated in liposarcoma) gene have been recently discovered to be associated with familial amyotrophic lateral sclerosis (FALS) in African, European and American populations. In a Japanese family with FALS, we found the R521C FUS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with FALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, followed by dysarthria, dysphagia, spasticity and muscle atrophy. The average age of death was 37.2 years. Neuropathological examination of the index case revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. We screened 40 FALS families in Japan and found 4 mutations (S513P, K510E, R514S, H517P) in exon 14 and 15 of FUS. Even in Asian races, FALS with FUS mutations may have the common characteristics of early onset, rapid progress and high penetrance rate, although in patients with the S513P mutation it was late-onset. Degeneration in multiple systems and cytoplasmic basophilic inclusion bodies were found in the autopsied cases. 3 Very recently, two groups of investigators reported the autosomal dominant form of FALS caused by fused in sarcoma (FUS) mutations, 4,5 following several reports of both familial and sporadic cases from Europe. 6-9 FUS is a nucleoprotein that functions in DNA and RNA metabolism. 10 In this study, we found a large Japanese FALS family with mutations in the FUS gene with the characteristics of early onset. In addition, we report four mutations of the FUS gene in Japanese FALS. CASE REPORT OF THE INDEX CASEThe patient (indicated by arrow in Figure 1a) was a Japanese man with autosomal dominant hereditary burden as described in a previous report. 11 His family history revealed 23 patients with FALS over four generations (Figure 1a). He developed muscle weakness of the distal part of the right upper extremity at age 30, followed by dysarthria, dysphagia, muscle weakness and atrophy in the four extremities, spasticity, hyperreflexia and Babinski's sign. His sensory, cerebellar and higher cortical functions were not affected. At age 31 (17 months after onset) he needed ventilatory support. At age 40, he died of bronchopneumonia. MATERIALS AND METHODSAll patients of FALS without the superoxide dismutase 1 mutation and healthy controls provided informed consent, after which DNA extraction and genotyping were performed using standard protocols as described elsewhere. 12 We sequenced all exons in 40 unrelated FALS families with the characteristics of an autosomal dominant trait in Japan. Sections of 5 mm thickness were taken from the midbrain of the index case and stained as described elsewhere. 5 Rabbit polyclonal anti-TDP-43 (ProteinTech, Chicago, IL, USA) and rabbit polyclonal anti-ubiquitin (Abcam, Cambridge, MA, USA) antibodies were used. The study was approved by the ethic...

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confidence: 83%

FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion

et al. 2010

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“…There is new evidence that TFs can interact directly with nascent RNA and recruit/inhibit chromatin modifying factors. 54 Wang et al recently showed that DNA damage leads to expression of non-coding RNA transcripts from the region upstream of the Ccnd1 promoter. The RNA binding protein, Translocated-in-Liposarcoma (TLS), binds to this nascent RNA and inhibits two histone acetyltransfeases leading to downregulation of the CCND1 mRNA.…”

Section: Possible Functions Of Divergent Rnasmentioning

confidence: 99%

Divergent transcription: A new feature of active promoters

Seila¹,

Core²,

Lis³

et al. 2009

Cell Cycle

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“…Martianov et al 29) demonstrated that noncoding RNA could directly interact with the general transcription factor IIB and format a stable complex, which could dissociate the preinitiation complex and major promoter, thus decreasing dihydrofolate reductase gene expression. Wang et al 30) found that ncRNACCND1 could recruit an RNA-binding protein chain); (c) Intronic: stemming from the introns of the protein-coding genes; (d) Intergenic: located between two protein-coding genes [termed long intergenic noncoding RNAs (lincRNAs)]; and (e) Bidirectional: produced by the upstream sequence and the opposite direction of protein-coding genes 3,14) .…”

Section: Transcriptional Regulationmentioning

confidence: 99%