GraphProt: modeling binding preferences of RNA-binding proteins

Maticzka, Daniel; Lange, Sita J.; Costa, Fabrizio; Backofen, Rolf

doi:10.1186/gb-2014-15-1-r17

Cited by 269 publications

(348 citation statements)

References 62 publications

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“…CTCF-binding RNAs were not enriched in any gene ontology (GO) terms, in keeping with CTCF’s role as global transcriptional regulator. Furthermore, analysis of CTCF CLIP peaks with the Multiple Em for Motif Elicitation (MEME) (Machanick and Bailey, 2011) and GraphProt (Maticzka et al, 2014) did not reveal a consensus motif, implying that CTCF recognizes RNA through secondary and/or tertiary structures instead of primary sequence.…”

Section: Resultsmentioning

confidence: 99%

Locus-Specific Targeting to the X Chromosome Revealed by the RNA Interactome of CTCF

et al. 2015

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CTCF is a master regulator that plays important roles in genome architecture and gene expression. How CTCF is recruited in a locus-specific manner is not fully understood. Evidence from epigenetic processes, such as X-chromosome inactivation (XCI), indicates that CTCF associates functionally with RNA. Using genome-wide approaches to investigate the relationship between its RNA interactome and epigenomic landscape, here we report that CTCF binds thousands of transcripts in mouse embryonic stem cells, many in close proximity to CTCF’s genomic binding sites. CTCF is a specific and high-affinity RNA-binding protein (Kd <1 nM). During XCI, CTCF differentially binds the active and inactive X-chromosomes and interacts directly with Tsix, Xite, and Xist RNAs. Tsix and Xite RNAs target CTCF to the X-inactivation center, thereby inducing homologous X-chromosome pairing. Our work elucidates one mechanism by which CTCF is recruited in a locus-specific manner and implicates CTCF-RNA interactions in long-range chromosomal interactions.

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Section: Resultsmentioning

confidence: 99%

Locus-Specific Targeting to the X Chromosome Revealed by the RNA Interactome of CTCF

et al. 2015

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“…A larger number of sequence variants in a given subset of the distribution decreases the probabilities and thus reduces the strength of the consensus. There are several approaches to delineate consensus motifs from binding site-data, obtained either in vitro or in vivo 70–77 . A consensus motif can guide a qualitative prediction of whether or not a protein binds well to a certain motif.…”

Section: Binding Modelsmentioning

confidence: 99%

Specificity and nonspecificity in RNA–protein interactions

Jankowsky

Harris

2015

Nat Rev Mol Cell Biol

240

251

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Gene expression is regulated by complex networks of interactions between RNAs and proteins. Proteins that interact with RNA have been traditionally viewed as either specific or non-specific; specific proteins interact preferentially with defined RNA sequence or structure motifs, whereas non-specific proteins interact with RNA sites devoid of such characteristics. Recent studies indicate that the binary “specific vs. non-specific” classification is insufficient to describe the full spectrum of RNA–protein interactions. Here, we review new methods that enable quantitative measurements of protein binding to large numbers of RNA variants, and the concepts aimed as describing resulting binding spectra: affinity distributions, comprehensive binding models and free energy landscapes. We discuss how these new methodologies and associated concepts enable work towards inclusive, quantitative models for specific and non-specific RNA–protein interactions.

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“…To confirm the agency of PTBP1 in ANXA7 exon 6 skipping, we sought PTBP1 binding sites on the ANXA7 minigene by analyzing cross-linking IP sequencing (CLIP-seq) data (61) on genome-wide PTB-RNA interactions and introducing mutations to specifically suppress PTBP1 binding to these regions (62). We created a binding model and trained it to extract 10 high-scoring binding-site candidates downstream, within, and upstream of exon 6 ( Figure 2J).…”

Section: Figurementioning

confidence: 99%

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

et al. 2014

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Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.

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GraphProt: modeling binding preferences of RNA-binding proteins

Cited by 269 publications

References 62 publications

Locus-Specific Targeting to the X Chromosome Revealed by the RNA Interactome of CTCF

Locus-Specific Targeting to the X Chromosome Revealed by the RNA Interactome of CTCF

Specificity and nonspecificity in RNA–protein interactions

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

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