26 results found
Bhalala OG, Nath AP, Inouye M, et al., 2018, Identification of expression quantitative trait loci associated with schizophrenia and affective disorders in normal brain tissue, PLOS GENETICS, Vol: 14, ISSN: 1553-7404
Bugai A, Quaresma AJC, Friedel C, et al., 2018, P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress
Cellular DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill-defined. Given the centrality of RNA polymerase II (Pol II) promoter-proximal pause release in transcriptional control, we evaluated its importance in DDR. Here we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates Pol II elongation and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb). This is mediated by genotoxic stress-enhanced binding of RBM7 to 7SK snRNA (7SK), the scaffold of the 7SK small nuclear ribonucleoprotein (7SK snRNP) which inhibits P-TEFb. In turn, P-TEFb relocates from 7SK snRNP to chromatin to induce transcription of short units including key DDR genes and multiple classes of non-coding RNAs. Critically, interfering with RBM7 or P-TEFb provokes cellular hypersensitivity to DNA damage-inducing agents through activation of apoptotic program. By alleviating the inhibition of P-TEFb, RBM7 thus facilitates Pol II elongation to enable a pro-survival transcriptional response that is crucial for cell fate upon genotoxic insult. Our work uncovers a new paradigm in stress-dependent control of Pol II pause release, and offers the promise for designing novel anti-cancer interventions using RBM7 and P-TEFb antagonists in combination with DNA-damaging chemotherapeutics.
Sibley CR, 2018, Individual Nucleotide Resolution UV Cross-Linking and Immunoprecipitation (iCLIP) to Determine Protein-RNA Interactions., Methods Mol Biol, Vol: 1649, Pages: 427-454
RNA-binding proteins (RBPs) interact with and determine the fate of many cellular RNA transcripts. In doing so they help direct many essential roles in cellular physiology, while their perturbed activity can contribute to disease etiology. In this chapter we detail a functional genomics approach, termed individual nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP), that can determine the interactions of RBPs with their RNA targets in high throughput and at nucleotide resolution. iCLIP achieves this by exploiting UV-induced covalent cross-links formed between RBPs and their target RNAs to both purify the RBP-RNA complexes under stringent conditions, and to cause reverse transcription stalling that then identifies the direct cross-link sites in the high throughput sequenced cDNA libraries.
Haberman N, Huppertz I, Attig J, et al., 2017, Insights into the design and interpretation of iCLIP experiments, GENOME BIOLOGY, Vol: 18, ISSN: 1474-760X
Haberman N, Huppertz I, Attig J, et al., 2017, Insights into the design and interpretation of iCLIP experiments (vol 18, pg 7, 2017), GENOME BIOLOGY, Vol: 18, ISSN: 1474-760X
Hall CE, Yao Z, Choi M, et al., 2017, Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS, CELL REPORTS, Vol: 19, Pages: 1739-1749, ISSN: 2211-1247
Ottens F, Boehm V, Sibley CR, et al., 2017, Transcript-specific characteristics determine the contribution of endo- and exonucleolytic decay pathways during the degradation of nonsense-mediated decay substrates, RNA, Vol: 23, Pages: 1224-1236, ISSN: 1355-8382
RNA-binding proteins (RBPs) interact with and determine the fate of many cellular RNA transcripts. In doing so they help direct many essential roles in cellular physiology, whilst their perturbed activity can contribute to disease aetiology. In this chapter we detail a functional genomics approach, termed individual nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP), that can determine the interactions of RBPs with their RNA targets in high throughput and at nucleotide resolution. iCLIP achieves this by exploiting UV-induced covalent crosslinks formed between RBPs and their target RNAs to both purify the RBP-RNA complexes under stringent conditions, and to cause reverse transcription stalling that then identifies the direct crosslink sites in the high throughput sequenced cDNA libraries.
Tyzack GE, Hall CE, Sibley CR, et al., 2017, A neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models, NATURE COMMUNICATIONS, Vol: 8, ISSN: 2041-1723
Beltran M, Yates CM, Skalska L, et al., 2016, The interaction of PRC2 with RNA or chromatin is mutually antagonistic, GENOME RESEARCH, Vol: 26, Pages: 896-907, ISSN: 1088-9051
Bhalala O, Nath A, Inouye M, et al., 2016, Identification of Brain Expression Quantitative Trait Loci Associated with Schizophrenia and Affective Disorders in Normal Brain Tissue
Schizophrenia and the affective disorders, here comprising bipolar disorder and major depressive disorder, are psychiatric illnesses that lead to significant morbidity and mortality worldwide. Whilst understanding of their pathobiology remains limited, large case-control studies have recently identified single nucleotide polymorphisms (SNPs) associated with these disorders. However, discerning the functional effects of these SNPs has been difficult as the associated causal genes are unknown. Here we evaluated whether schizophrenia and affective disorder associated-SNPs are correlated with gene expression within human brain tissue. Specifically, to identify expression quantitative trait loci (eQTLs), we leveraged disorder-associated SNPs identified from six Psychiatric Genomics Consortium and CONVERGE Consortium studies with gene expression levels in post-mortem, neurologically-normal tissue from two independent human brain tissue expression datasets (UK Brain Expression Consortium (UKBEC) and Genotype-Tissue Expression (GTEx)). We identified 6 188 and 16 720 cis-acting SNPs exceeding genome-wide significance (p<5x10-8) in the UKBEC and GTEx datasets, respectively. 1 288 cis-eQTLs were significant in a meta-analysis leveraging overlapping brain regions and were associated with expression of 15 genes, including three non-coding RNAs. One cis-eQTL, rs16969968, results in a functionally disruptive missense mutation in CHRNA5, a schizophrenia-implicated gene. Meta-analysis identified 297 trans-eQTLs associated with 24 genes that were significant in a region-specific manner. Importantly, comparing across tissues, we find that blood eQTLs largely do not capture brain cis-eQTLs. This study identifies putatively causal genes whose expression in region-specific brain tissue may contribute to the risk of schizophrenia and affective disorders.
Sibley CR, Blazquez L, Ule J, 2016, Lessons from non-canonical splicing, NATURE REVIEWS GENETICS, Vol: 17, Pages: 407-421, ISSN: 1471-0056
Wickramasinghe VO, Gonzalez-Porta M, Perera D, et al., 2015, Regulation of constitutive and alternative mRNA splicing across the human transcriptome by PRPF8 is determined by 5 ' splice site strength, GENOME BIOLOGY, Vol: 16, ISSN: 1474-760X
Huppertz I, Attig J, D'Ambrogio A, et al., 2014, iCLIP: Protein-RNA interactions at nucleotide resolution, METHODS, Vol: 65, Pages: 274-287, ISSN: 1046-2023
Sibley CR, 2014, Regulation of gene expression through production of unstable mRNA isoforms, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 42, Pages: 1196-1205, ISSN: 0300-5127
Modic M, Ule J, Sibley CR, 2013, CLIPing the brain: Studies of protein-RNA interactions important for neurodegenerative disorders, MOLECULAR AND CELLULAR NEUROSCIENCE, Vol: 56, Pages: 429-435, ISSN: 1044-7431
Curtis HJ, Sibley CR, Wood MJA, 2012, Mirtrons, an emerging class of atypical miRNA, WILEY INTERDISCIPLINARY REVIEWS-RNA, Vol: 3, Pages: 617-632, ISSN: 1757-7004
Patani R, Sibley CR, Chandran S, et al., 2012, Using human pluripotent stem cells to study post-transcriptional mechanisms of neurodegenerative diseases, BRAIN RESEARCH, Vol: 1462, Pages: 129-138, ISSN: 0006-8993
Seow Y, Sibley CR, Wood MJA, 2012, Artificial mirtron-mediated gene knockdown: Functional DMPK silencing in mammalian cells, RNA-A PUBLICATION OF THE RNA SOCIETY, Vol: 18, Pages: 1328-1337, ISSN: 1355-8382
Sibley CR, Attig J, Ule J, 2012, The greatest catch: big game fishing for mRNA-bound proteins, GENOME BIOLOGY, Vol: 13, ISSN: 1465-6906
Sibley CR, Seow Y, Curtis H, et al., 2012, Silencing of Parkinson's disease-associated genes with artificial mirtron mimics of miR-1224, NUCLEIC ACIDS RESEARCH, Vol: 40, Pages: 9863-9875, ISSN: 0305-1048
Sibley CR, Seow Y, Saayman S, et al., 2012, The biogenesis and characterization of mammalian microRNAs of mirtron origin, NUCLEIC ACIDS RESEARCH, Vol: 40, Pages: 438-448, ISSN: 0305-1048
Sibley CR, Wood MJA, 2011, Identification of Allele-Specific RNAi Effectors Targeting Genetic Forms of Parkinson's Disease, PLOS ONE, Vol: 6, ISSN: 1932-6203
Sibley CR, Wood MJA, 2011, The miRNA pathway in neurological and skeletal muscle disease: implications for pathogenesis and therapy, JOURNAL OF MOLECULAR MEDICINE-JMM, Vol: 89, Pages: 1065-1077, ISSN: 0946-2716
Sibley CR, Seow Y, Wood MJA, 2010, Novel RNA-based Strategies for Therapeutic Gene Silencing, MOLECULAR THERAPY, Vol: 18, Pages: 466-476, ISSN: 1525-0016
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