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Rna splicing

Julie Rodor, David R FitzPatrick, Eduardo Eyras, Javier F Cáceres
Mutations in the RNA-binding protein, RBM10, result in a human syndromic form of cleft palate, termed TARP syndrome. A role for RBM10 in alternative splicing regulation has been previously demonstrated in human cell lines. To uncover the cellular functions of RBM10 in a cell line that is relevant to the phenotype observed in TARP syndrome, we used iCLIP to identify its endogenous RNA targets in a mouse embryonic mandibular cell line. We observed that RBM10 binds to pre-mRNAs with significant enrichment in intronic regions, in agreement with a role for this protein in pre-mRNA splicing...
October 20, 2016: RNA Biology
Laure D Sultan, Daria Mileshina, Felix Grewe, Katarzyna Rolle, Sivan Abudraham, Paweł Głodowicz, Adnan Khan Niazi, Ido Keren, Sofia Shevtsov, Liron Klipcan, Jan Barciszewski, Jeffrey P Mower, Andre Dietrich, Oren Ostersetzer
Group II introns are large catalytic RNAs that are ancestrally related to nuclear spliceosomal introns. Sequences corresponding to group II RNAs are found in many prokaryotes and are particularly prevalent within plants organellar genomes. Proteins encoded within the introns themselves (maturases) facilitate the splicing of their own host pre-RNAs. Mitochondrial introns in plants have diverged considerably in sequence and have lost their maturases. In angiosperms, only a single maturase has been retained in the mitochondrial DNA: the matR gene found within NADH dehydrogenase 1 (nad1) intron 4...
October 19, 2016: Plant Cell
Juntao Liu, Ting Yu, Tao Jiang, Guojun Li
Transcriptome assemblers aim to reconstruct full-length transcripts from RNA-seq data. We present TransComb, a genome-guided assembler developed based on a junction graph, weighted by a bin-packing strategy and paired-end information. A newly designed extension method based on weighted junction graphs can accurately extract paths representing expressed transcripts, whether they have low or high expression levels. Tested on both simulated and real datasets, TransComb demonstrates significant improvements in both recall and precision over leading assemblers, including StringTie, Cufflinks, Bayesembler, and Traph...
October 19, 2016: Genome Biology
Jason T Huff, Daniel Zilberman, Scott W Roy
The discovery of introns four decades ago was one of the most unexpected findings in molecular biology. Introns are sequences interrupting genes that must be removed as part of messenger RNA production. Genome sequencing projects have shown that most eukaryotic genes contain at least one intron, and frequently many. Comparison of these genomes reveals a history of long evolutionary periods during which few introns were gained, punctuated by episodes of rapid, extensive gain. However, although several detailed mechanisms for such episodic intron generation have been proposed, none has been empirically supported on a genomic scale...
October 19, 2016: Nature
Jimena Giudice, Zheng Xia, Wei Li, Thomas A Cooper
The RNA binding protein Celf1 regulates alternative splicing in the nucleus and mRNA stability and translation in the cytoplasm. Celf1 is strongly down-regulated during mouse postnatal heart development. Its re-induction in adults induced severe heart failure and reversion to fetal splicing and gene expression patterns. However, the impact of Celf1 depletion on cardiac transcriptional and posttranscriptional dynamics in neonates has not been addressed. We found that homozygous Celf1 knock-out neonates exhibited cardiac dysfunction not observed in older homozygous animals, although homozygous mice are smaller than wild type littermates throughout development...
October 19, 2016: Scientific Reports
Suzanne Miller, Amanda P Henry, Emily Hodge, Alexander K Kheirallah, Charlotte K Billington, Tracy L Rimington, Sangita K Bhaker, Ma'en Obeidat, Erik Melén, Simon K Merid, Caroline Swan, Catherine Gowland, Carl P Nelson, Ceri E Stewart, Charlotte E Bolton, Iain Kilty, Anders Malarstig, Stuart G Parker, Miriam F Moffatt, Andrew J Wardlaw, Ian P Hall, Ian Sayers
INTRODUCTION: Genome-Wide Association Studies have identified associations between lung function measures and Chronic Obstructive Pulmonary Disease (COPD) and chromosome region 6p21 containing the gene for the Advanced Glycation End Product Receptor (AGER, encoding RAGE). We aimed to (i) characterise RAGE expression in the lung, (ii) identify AGER transcripts, (iii) ascertain if SNP rs2070600 (Gly82Ser C/T) is associated with lung function and serum sRAGE levels and (iv) identify whether the Gly82Ser variant is functionally important in altering sRAGE levels in an airway epithelial cell model...
2016: PloS One
Rei Yoshimoto, Daisuke Kaida, Masaaki Furuno, A Maxwell Burroughs, Shohei Noma, Harukazu Suzuki, Yumi Kawamura, Yoshihide Hayashizaki, Akila Mayeda, Minoru Yoshida
Spliceostatin A (SSA) is a methyl ketal derivative of FR901464, a potent antitumor compound isolated from a culture broth of Pseudomonas sp. no. 2663. These compounds selectively bind to the essential spliceosome component SF3b, a subcomplex of the U2 snRNP, to inhibit pre-mRNA splicing. However, the mechanism of SSA's antitumor activity is unknown. It is noteworthy that SSA causes accumulation of a truncated form of the CDK inhibitor protein p27 translated from CDKN1B pre-mRNA, which is involved in SSA-induced cell-cycle arrest...
October 17, 2016: RNA
Pravin Kumar Ankush Jagtap, Divita Garg, Tobias G Kapp, Cindy L Will, Oliver Demmer, Reinhard Luhrmann, Horst Kessler, Michael Sattler
U2AF homology motifs (UHMs) are atypical RNA Recognition Motif (RRM) domains that mediate critical protein-protein interactions during the regulation of alternative pre-mRNA splicing and other processes. The recognition of UHM domains by UHM Ligand Motif (ULM) peptide sequences plays important roles during early steps of spliceosome assembly. Splicing factor 45 kDa (SPF45) is an alternative splicing factor implicated in breast and lung cancer and splicing regulation of apoptosis-linked pre-mRNAs by SPF45 was shown to depend on interactions of its UHM domain with ULM motifs in constitutive splicing factors...
October 18, 2016: Journal of Medicinal Chemistry
O Sakiragaoglu, A L Munn
To inhibit telomerase activity, a construct which contains artificial introns in the enhanced green fluorescent protein (EGFP) gene that encodes small hairpin RNA (shRNA) sequences that target human telomerase reverse transcriptase (hTERT) gene expression was designed and tested for its effect on lung cancer cell line. On intron splicing from the construct, intronic sequences were released and formed shRNA in the cells. After transfection of the construct, hTERT mRNA expression decreased by approximately 55 % in A549 cells...
October 17, 2016: Molecular Biotechnology
He Wang, Yanmei Chen, Xinzhong Li, Guojun Chen, Lintao Zhong, Gangbing Chen, Yulin Liao, Wangjun Liao, Jianping Bin
Alternative splicing (AS) drives determinative changes during mouse heart development. Recent high-throughput technological advancements have facilitated genome-wide AS, while its analysis in human foetal heart transition to the adult stage has not been reported. Here, we present a high-resolution global analysis of AS transitions between human foetal and adult hearts. RNA-sequencing data showed extensive AS transitions occurred between human foetal and adult hearts, and AS events occurred more frequently in protein-coding genes than in long non-coding RNA (lncRNA)...
October 18, 2016: Scientific Reports
Christina R Tyler, Matthew T Labrecque, Elizabeth R Solomon, Xun Guo, Andrea M Allan
Exposure to arsenic, a common environmental toxin found in drinking water, leads to a host of neurological pathologies. We have previously demonstrated that developmental exposure to a low level of arsenic (50ppb) alters epigenetic processes that underlie deficits in adult hippocampal neurogenesis leading to aberrant behavior. It is unclear if arsenic impacts the programming and regulation of embryonic neurogenesis during development when exposure occurs. The master negative regulator of neural-lineage, REST/NRSF, controls the precise timing of fate specification and differentiation of neural stem cells (NSCs)...
October 14, 2016: Neurotoxicology and Teratology
David S Lynch, Wei Jia Zhang, Rahul Lakshmanan, Justin A Kinsella, Günes Altiokka Uzun, Merih Karbay, Zeynep Tüfekçioglu, Hasmet Hanagasi, Georgina Burke, Nicola Foulds, Simon R Hammans, Anupam Bhattacharjee, Heather Wilson, Matthew Adams, Mark Walker, James A R Nicoll, Jeremy Chataway, Nick Fox, Indran Davagnanam, Rahul Phadke, Henry Houlden
Importance: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations...
October 17, 2016: JAMA Neurology
Zachery R Reichert, Maha Hussain
The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival...
September 2016: Cancer Journal
Michael Saul, Petra Majdak, Samuel Perez, Matthew Reilly, Theodore Garland, Justin S Rhodes
Though exercise is critical for health, many lack the motivation to exercise, and it is unclear how motivation might be increased. To uncover the molecular underpinnings of increased motivation for exercise, we analyzed the transcriptome of the striatum in four mouse lines selectively bred for high voluntary wheel running and four non-selected control lines. The striatum was dissected and RNA was extracted and sequenced from four individuals of each line. We found multiple genes and gene systems with strong relationships to both selection and running history over the previous 6 days...
October 17, 2016: Genes, Brain, and Behavior
Madeleine Berger, Alin Mirel Puinean, Emma Randall, Christoph T Zimmer, Wellington M Silva, Pablo Bielza, Linda M Field, David Hughes, Ian Mellor, Keywan Hassani-Pak, Herbert A A Siqueira, Martin S Williamson, Chris Bass
Many genes increase coding capacity by alternate exon usage. The gene encoding the insect nicotinic acetylcholine receptor (nAChR) α6 subunit, target of the bio-insecticide spinosad, is one example of this and expands protein diversity via alternative splicing of mutually exclusive exons. Here we show that spinosad resistance in the tomato leafminer, Tuta absoluta is associated with aberrant regulation of splicing of Taα6 resulting in a novel form of insecticide resistance mediated by exon skipping. Sequencing of the α6 subunit cDNA from spinosad selected and unselected strains of T...
October 17, 2016: Molecular Ecology
Michele Balsamo, Chandrani Mondal, Guillaume Carmona, Leslie M McClain, Daisy N Riquelme, Jenny Tadros, Duan Ma, Eliza Vasile, John S Condeelis, Douglas A Lauffenburger, Frank B Gertler
During tumor progression, alternative splicing gives rise to different Mena protein isoforms. We analyzed how Mena11a, an isoform enriched in epithelia and epithelial-like cells, affects Mena-dependent regulation of actin dynamics and cell behavior. While other Mena isoforms promote actin polymerization and drive membrane protrusion, we find that Mena11a decreases actin polymerization and growth factor-stimulated membrane protrusion at lamellipodia. Ectopic Mena11a expression slows mesenchymal-like cell motility, while isoform-specific depletion of endogenous Mena11a in epithelial-like tumor cells perturbs cell:cell junctions and increases membrane protrusion and overall cell motility...
October 17, 2016: Scientific Reports
John G Conboy
The Rbfox genes encode an ancient family of sequence-specific RNA binding proteins (RBPs) that are critical developmental regulators in multiple tissues including skeletal muscle, cardiac muscle, and brain. The hallmark of Rbfox proteins is a single high-affinity RRM domain, highly conserved from insects to humans, that binds preferentially to UGCAUG motifs at diverse regulatory sites in pre-mRNA introns, mRNA 3'UTRs, and pre-miRNAs hairpin structures. Versatile regulatory circuits operate on Rbfox pre-mRNA and mRNA to ensure proper expression of Rbfox1 protein isoforms, which then act on the broader transcriptome to regulate alternative splicing networks, mRNA stability and translation, and microRNA processing...
October 17, 2016: Wiley Interdisciplinary Reviews. RNA
Maurizio Cirilli, Oxana Bereshchenko, Olga Ermakova, Claus Nerlov
BACKGROUND: C/EBPa and C/EBPb are transcription factors with tissue specific expression regulating several important cellular processes. They work by recruiting protein complexes to a common DNA recognition motif and both are able to compensate each other's absence in many cell types, thus showing functional redundancy. They also play distinct roles in specific cellular pathways and their abnormal functioning gives raise to different human pathologies. METHODS: To investigate the molecular basis of C/EBPa and C/EBPb specificity and redundancy we characterized their in vivo protein-protein interaction networks by Tandem Affinity Purification and Mass Spectrometry...
October 13, 2016: Biochimica et Biophysica Acta
Veenu Tripathi, Katherine M Sixt, Shaojian Gao, Xuan Xu, Jing Huang, Roberto Weigert, Ming Zhou, Ying E Zhang
In advanced stages of cancers, TGF-β promotes tumor progression in conjunction with inputs from receptor tyrosine kinase pathways. However, mechanisms that underpin the signaling cooperation and convert TGF-β from a potent growth inhibitor to a tumor promoter are not fully understood. We report here that TGF-β directly regulates alternative splicing of cancer stem cell marker CD44 through a phosphorylated T179 of SMAD3-mediated interaction with RNA-binding protein PCBP1. We show that TGF-β and EGF respectively induce SMAD3 and PCBP1 to colocalize in SC35-positive nuclear speckles, and the two proteins interact in the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly in favor of expressing the mesenchymal isoform CD44s over the epithelial isoform CD44E...
October 4, 2016: Molecular Cell
Ru Zheng, Yue Li, Huiying Sun, Xiaoyin Lu, Bao-Fa Sun, Rui Wang, Lina Cui, Cheng Zhu, Hai-Yan Lin, Hongmei Wang
The syncytiotrophoblast (STB) plays a key role in maintaining the function of the placenta during human pregnancy. However, the molecular network that orchestrates STB development remains elusive. The aim of this study was to obtain broad and deep insight into human STB formation via transcriptomics. We adopted RNA sequencing (RNA-Seq) to investigate genes and isoforms involved in forskolin (FSK)-induced fusion of BeWo cells. BeWo cells were treated with 50 μM FSK or dimethylsulfoxide (DMSO) as a vehicle control for 24 and 48 h, and the mRNAs at 0, 24 and 48 h was sequenced...
October 14, 2016: Reproduction: the Official Journal of the Society for the Study of Fertility
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