iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution

König, Julian; Zarnack, Kathi; Rot, Gregor; Curk, Tomaž; Kayikci, Melis; Zupan, Blaž; Turner, Daniel J.; Luscombe, Nicholas M.; Ule, Jernej

doi:10.1038/nsmb.1838

Cited by 1,019 publications

(1,185 citation statements)

References 34 publications

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“…Accumulation of some dsRNA regions was indeed observed after HNRNPC knock‐down. These elevated dsRNA species were mostly found in introns, corroborating known transcriptome‐wide HNRNPC binding regions (Konig et al , 2010; Zarnack et al , 2013). This differs from previous observation of elevated dsRNA derived from normally hypermethylated endogenous retroviruses (ERVs) that are activated by anti‐tumor inhibitors to trigger the IFN response as a therapeutic approach (Chiappinelli et al , 2015; Roulois et al , 2015; Goel et al , 2017).…”

Section: Introductionsupporting

confidence: 70%

“…Heterogeneous nuclear ribonucleoprotein C has been well characterized for its function in binding to the intron regions of pre‐mRNA and regulating silencing or inclusion of the introns (Konig et al , 2010). Further studies revealed that HNRNPC is essential for repression of aberrant exonization of the Alu elements in the introns, and loss of HNRNPC resulted in abnormal inclusion of Alu in the transcripts (Zarnack et al , 2013).…”

Section: Resultsmentioning

confidence: 99%

“…The RBP HNRNPC has attracted much attention in the recent years, for its multiplex functions in regulating pre‐mRNA splicing (Konig et al , 2010; Zarnack et al , 2013), mRNA stabilization (Shetty, 2005), length‐dependent exportation (McCloskey et al , 2012), stability and translation (Holcik et al , 2003; Kim et al , 2003; Schepens et al , 2007), etc. Although HNRNPC has been shown to regulate multiple cancer‐related genes, mostly through RNA‐related processes, understanding about the accountable machinery for the function of HNRNPC in tumors is still limited.…”

Section: Discussionmentioning

confidence: 99%

“…This differs from previous observation of elevated dsRNA derived from normally hypermethylated endogenous retroviruses (ERVs) that are activated by anti‐tumor inhibitors to trigger the IFN response as a therapeutic approach (Chiappinelli et al , 2015; Roulois et al , 2015; Goel et al , 2017). Heterogeneous nuclear ribonucleoprotein C is well known for its function in regulating RNA splicing by binding with introns, especially the introns containing Alu (Konig et al , 2010; Zarnack et al , 2013). Indeed, almost all the up‐regulated dsRNA regions contain Alu or Alu fragments.…”

Section: Introductionmentioning

confidence: 99%

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Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

et al. 2018

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Elevated expression of RNA binding protein HNRNPC has been reported in cancer cells, while the essentialness and functions of HNRNPC in tumors were not clear. We showed that repression of HNRNPC in the breast cancer cells MCF7 and T47D inhibited cell proliferation and tumor growth. Our computational inference of the key pathways and extensive experimental investigations revealed that the cascade of interferon responses mediated by RIG‐I was responsible for such tumor‐inhibitory effect. Interestingly, repression of HNRNPC resulted in accumulation of endogenous double‐stranded RNA (dsRNA), the binding ligand of RIG‐I. These up‐regulated dsRNA species were highly enriched by Alu sequences and mostly originated from pre‐mRNA introns that harbor the known HNRNPC binding sites. Such source of dsRNA is different than the recently well‐characterized endogenous retroviruses that encode dsRNA. In summary, essentialness of HNRNPC in the breast cancer cells was attributed to its function in controlling the endogenous dsRNA and the down‐stream interferon response. This is a novel extension from the previous understandings about HNRNPC in binding with introns and regulating RNA splicing.

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Section: Introductionsupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

et al. 2018

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“…iCLIP was performed as detailed by König et al (2010). Dissected forebrain ( RRM2mut ) or adult brain ( LCDmut ) were homogenised in phosphate‐buffered saline (PBS) and UV‐crosslinked 4× at 100 mJ/cm 2 at a wavelength of 254 nm ( RRM2mut n = 2, LCDmut n = 1–2).…”

Section: Methodsmentioning

confidence: 99%

Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

et al. 2018

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TDP‐43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP‐43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C‐terminal domain of TDP‐43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP‐43 loss‐ and gain‐of‐function effects. TDP‐43 gain‐of‐function effects in these mice reveal a novel category of splicing events controlled by TDP‐43, referred to as “skiptic” exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain‐of‐function mutation in endogenous Tardbp causes an adult‐onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain‐of‐function and skiptic exons in ALS patient‐derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP‐43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages.

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Spatially and temporally regulating translation via mRNA‐binding proteins in cellular and neuronal function

2017

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Edited by Wilhelm JustCoordinated regulation of mRNA localization and local translation are essential steps in cellular asymmetry and function. It is increasingly evident that mRNA-binding proteins play critical functions in controlling the fate of mRNA, including when and where translation occurs. In this review, we discuss the robust and complex roles that mRNA-binding proteins play in the regulation of local translation that impact cellular function in vertebrates. First, we discuss the role of local translation in cellular polarity and possible links to vertebrate development and patterning. Next, we discuss the expanding role for local protein synthesis in neuronal development and function, with special focus on how a number of neurological diseases have given us insight into the importance of translational regulation. Finally, we discuss the everincreasing set of tools to study regulated translation and how these tools will be vital in pushing forward and addressing the outstanding questions in the field.

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iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution

Cited by 1,019 publications

References 34 publications

Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

Spatially and temporally regulating translation via mRNA‐binding proteins in cellular and neuronal function

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