Global Profiling of Alternative Splicing Events and Gene Expression Regulated by hnRNPH/F

Wang, Erming; Aslanzadeh, Vahid; Papa, Filomena; Zhu, Haiyan; Grange, Pierre de la; Cambi, Franca

doi:10.1371/journal.pone.0051266

Cited by 42 publications

(65 citation statements)

References 42 publications

(77 reference statements)

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“…In general binding of hnRNP H1 to intronic regions particularly in the region downstream of the 5 0 splice site usually results in enhance use of the splice site. 34,35 This is a possible mechanism by which hnRNP H1 increases the inclusion of exon 16 as RNA chromatography demonstrated hnRNP H1 binding to the introns surrounding exon 16 with particularly strong binding to intron 16. Indeed there are predicted binding sites for hnRNP H1 in introns 15 and 16 in the regions covered by H5 and H6 oligonucleotides.…”

Section: Discussionmentioning

confidence: 99%

SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells

et al. 2015

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Keywords: breast cancer, HER2, hnRNP H1, RNA binding proteins, splice variants, SRSF3Overexpression of the oncogene HER2 occurs in 20-30% of invasive breast cancer and is associated with poor prognosis. A number of different splice variants of HER2 have been identified which produce functionally different proteins. Previously these splice variants have been investigated separately, but in the present study we collectively look at the expression and regulation of a group of HER2 splice variants produced by a splicing hotspot. Initial investigation in a cohort of tumor samples showed large variations in HER2 variant expression between patient samples. RNA interference studies identified 2 splicing factors involved in the regulation of splicing within this region, hnRNP H1 and SRSF3. siRNA targeting hnRNP H1 increases levels of X5 and the oncogenic variant D16HER2. Furthermore RNA chromatography assays demonstrated binding of hnRNP H1 to RNA in this region. Additionally the proto-oncogene SRSF3 was also identified as an important regulator of splicing with SRSF3 knockdown resulting in changes in all the splice variants located at the hotspot. Most notably knockdown of SRSF3 resulted in a switch from the oncogenic D16HER2 to p100 which inhibits cell proliferation. Binding of SRSF3 to RNA within this region was also demonstrated by RNA chromatography and more specifically 2 SRSF3 binding sites were identified within exon 15. SRSF3 and hnRNP H1 are the first splicing factors identified which regulate the production of these functionally distinct HER2 splice variants and therefore maybe important for the regulation of HER2 signaling.

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Section: Discussionmentioning

confidence: 99%

SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells

et al. 2015

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“…The significance of HNRNPH in controlling alternative splicing of neural genes was previously shown in oligodendrocytes. 55,56 Of note, HNRNPH1 regulates alternative splicing of the neuron-specific exon N of REST. 57 The role of HNRNPH on TRF2 splicing in neuronal differentiation was tested in two model systems.…”

Section: Nuclear Role Of Trf2mentioning

confidence: 99%

The long and the short of TRF2 in neurogenesis

et al. 2016

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Gene expression patterns change dramatically during neuronal development. Proliferating cells, including neural stem cells (NSCs), express telomere repeat-binding factor 2 (TRF2), a nuclear protein that associates with telomeric proteins, DNA, and RNA telomeres. In NSCs TRF2 also binds to the transcription regulator REST to facilitate repression of numerous neuron-specific genes, thereby keeping the NSCs in a selfrenewing state. Upon neuronal differentiation, TRF2 levels decline, REST-regulated neuronal genes are derepressed, and a short isoform of TRF2 arises (TRF2-S) which localizes in the cytoplasm, associates with different subsets of proteins and transcripts, and mobilizes axonal G-rich mRNAs. We recently identified two RNA-binding proteins, HNRNPH1 and H2 (referred to jointly as HNRNPH due to their high homology), which mediate the alternative splicing of an exon required for the expression of full-length TRF2. As HNRNPH levels decline during neurogenesis, TRF2 abundance decreases and TRF2-S accumulates. Here, we discuss the shared and unique functions of TRF2 and TRF2-S, the distinct subcellular compartment in which each isoform resides, the subsets of proteins and nucleic acids with which each interacts, and the functional consequences of these ribonucleoprotein interactions. This paradigm illustrates the dynamic mechanisms through which splicing regulation by factors like HNRNPH enable distinct protein functions as cells adapt to developmental programs such as neurogenesis.

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“…This protein tends to form a heterodimer with hnRNP F and shows preference for G-rich tracts of RNA. 2,[6][7][8] It has also been shown that hnRNP H1 interacts with the DGCR8 complex and facilitates microRNA processing in HeLa cells. 9 The impact of hnRNP H1 binding on alternative splicing has been associated with several diseases, such as cystic fibrosis, 10 congenital myasthemic syndrome, 11 and amyotrophic lateral sclerosis (ALS).…”

Section: Introductionmentioning

confidence: 99%

“…18 In addition to these targeted analyses, genome-wide studies have revealed hnRNP H1s role, in conjunction with hnRNP F, in promoting both exon inclusion and skipping. 8 Other recent studies have linked hnRNP H1 to alternative cleavage and polyadenylation, 6 and established the cooperative roles of the hnRNP proteins in the regulation of splicing. 2 By employing a combined strategy with 4 different high-throughput approaches, we were able to provide a more refined and accurate picture for hnRNP H1 in splicing regulation and extend our understanding of its participation in polyadenylation and mRNA decay.…”

Section: Introductionmentioning

confidence: 99%

High-throughput analyses of hnRNP H1 dissects its multi-functional aspect

et al. 2016

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ABSTRACThnRNPs are polyvalent RNA binding proteins that have been implicated in a range of regulatory roles including splicing, mRNA decay, translation, and miRNA metabolism. A variety of genome wide studies have taken advantage of methods like CLIP and RIP to identify the targets and binding sites of RNA binding proteins. However, due to the complex nature of RNA-binding proteins, these studies are incomplete without assays that characterize the impact of RBP binding on mRNA target expression. Here we used a suite of high-throughput approaches (RIP-Seq, iCLIP, RNA-Seq and shotgun proteomics) to provide a comprehensive view of hnRNP H1s ensemble of targets and its role in splicing, mRNA decay, and translation. The combination of RIP-Seq and iCLIP allowed us to identify a set of 1,086 high confidence target transcripts. Binding site motif analysis of these targets suggests the TGGG tetramer as a prevalent component of hnRNP H1 binding motif, with particular enrichment around intronic hnRNP H1 sites. Our analysis of the target transcripts and binding sites indicates that hnRNP H1s involvement in splicing is 2-fold: it directly affects a substantial number of splicing events, but also regulates the expression of major components of the splicing machinery and other RBPs with known roles in splicing regulation. The identified mRNA targets displayed function enrichment in MAPK signaling and ubiquitin mediated proteolysis, which might be main routes by which hnRNP H1 promotes tumorigenesis.

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Global Profiling of Alternative Splicing Events and Gene Expression Regulated by hnRNPH/F

Cited by 42 publications

References 42 publications

SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells

SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells

The long and the short of TRF2 in neurogenesis

High-throughput analyses of hnRNP H1 dissects its multi-functional aspect

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