The splicing regulators Esrp1 and Esrp2 direct an epithelial splicing program essential for mammalian development

Bebee, Thomas W.; Park, Juw Won; Sheridan, Katherine I; Warzecha, Claude C.; Cieply, Benjamin; Rohacek, Alex M; Xing, Yi; Carstens, Russ P.

doi:10.7554/elife.08954

Cited by 128 publications

(241 citation statements)

References 77 publications

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“…The mammalian ESRPs and their orthologs in chicken, D. melanogaster, and C. elegans comprise three RRMs and display significant phylogenetic sequence conservation within these domains, particularly within the first RRM (Warzecha et al 2009a). Mice with ablation of Esrp1 develop cleft lip and palate, whereas tissue-specific ablation in the epidermis revealed ESRP1's requirement for establishing a proper skin barrier (Bebee et al 2015). Loss of both Esrp1 and Esrp2 results in widespread developmental defects (Bebee et al 2015).…”

Section: Other Hnrnpsmentioning

confidence: 99%

“…Mice with ablation of Esrp1 develop cleft lip and palate, whereas tissue-specific ablation in the epidermis revealed ESRP1's requirement for establishing a proper skin barrier (Bebee et al 2015). Loss of both Esrp1 and Esrp2 results in widespread developmental defects (Bebee et al 2015). ESRPs regulate alternative splicing events associated with epithelial cell phenotypes, and both proteins are down-regulated during the epithelial-mesenchymal transition (EMT) (Warzecha et al 2009a).…”

Section: Other Hnrnpsmentioning

confidence: 99%

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Splicing-factor alterations in cancers

Anczuków

Krainer

2016

RNA

218

247

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Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic splicing events or their upstream splicing regulators.

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Section: Other Hnrnpsmentioning

confidence: 99%

Section: Other Hnrnpsmentioning

confidence: 99%

Splicing-factor alterations in cancers

Anczuków

Krainer

2016

RNA

218

247

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“…We performed motif enrichment analysis as described previously to identify binding sites of splicing factors and other RNA binding proteins (RBPs) that were significantly enriched in differential exon skipping events (33). We used 115 known binding sites (motifs) of RBPs from the literature (8,27,(34)(35)(36), including well-known splicing factors.…”

Section: Motif Enrichment Analysismentioning

confidence: 99%

“…If an alternative exon didn't show splicing changes (rMATS FDR of Ͼ50%, maxPSI of Ͼ15%, and minPSI of Ͻ85%) and it was from highly expressed genes (average FPKM of Ͼ5.0 in at least one group), we classified it as a control alternative exon. As described previously, we examined the exon body, 250 bp of upstream and downstream introns, flanking exons, and 250-bp intronic regions of flanking exons to assign motif scores (33). Motif scores were assigned as the overall percentage of nucleotides covered by any of 12 ESRP motifs within a 50-bp sliding window.…”

Section: Motif Enrichment Analysismentioning

confidence: 99%

Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

Yang

Park

Bebee

et al. 2016

Molecular and Cellular Biology

Self Cite

123

165

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fThe epithelial-to-mesenchymal transition (EMT) is an essential biological process during embryonic development that is also implicated in cancer metastasis. While the transcriptional regulation of EMT has been well studied, the role of alternative splicing (AS) regulation in EMT remains relatively uncharacterized. We previously showed that the epithelial cell-type-specific proteins epithelial splicing regulatory proteins 1 (ESRP1) and ESRP2 are important for the regulation of many AS events that are altered during EMT. However, the contributions of the ESRPs and other splicing regulators to the AS regulatory network in EMT require further investigation. Here, we used a robust in vitro EMT model to comprehensively characterize splicing switches during EMT in a temporal manner. These investigations revealed that the ESRPs are the major regulators of some but not all AS events during EMT. We determined that the splicing factor RBM47 is downregulated during EMT and also regulates numerous transcripts that switch splicing during EMT. We also determined that Quaking (QKI) broadly promotes mesenchymal splicing patterns. Our study highlights the broad role of posttranscriptional regulation during the EMT and the important role of combinatorial regulation by different splicing factors to fine tune gene expression programs during these physiological and developmental transitions.A lternative splicing (AS) is a process by which a single gene transcript can be differentially spliced to yield numerous splice variants that can encode different protein isoforms and thereby greatly expand the protein coding capacity of the genome. Nearly all human genes are alternatively spliced, and cell-typespecific protein isoforms have been shown to be functionally essential for cell fate and viability (1-3). This process is under complex regulation by various cis elements in pre-mRNAs and their cognate binding partners, mainly RNA-binding proteins (RBPs). Splicing-regulatory RBPs recruited to their respective binding sites can have positive or negative effects on the splicing of different exons or splice sites. Many RBPs with largely ubiquitous expression in different tissues and cells have been shown to have broad impacts on splicing and important cell functions, such as SR and hnRNP protein families (4). However, several tissue-specific RBPs, such as NOVA, PTBP2 (nPTB), MBNL, and RBFOX proteins, have recently been described as having important roles as essential regulators of tissue-or cell-type-specific splicing (5-9). In order to further define a "splicing code" that controls broad patterns of tissue-specific splicing, as well as those that occur during developmental transitions, it is essential to characterize in greater detail how these tissue-specific regulators fine-tune AS programs combinatorially with more ubiquitously expressed splicing regulators (10).The epithelial-to-mesenchymal transition (EMT) is a process by which epithelial cells transdifferentiate into mesenchymal cells, which involves extensive changes at the cellular ...

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“…One of the mechanisms by which the requirement of the metastasizing cell is met is by increasing the protein diversity by alternative splicing. It is therefore significant that mitochondrial retrograde signaling modulates the expression of the Epithelial Splicing Regulatory Protein (ESRP)-1, which regulates the alternative splicing of a wide array of gene sets involved in inducing EMT [38, [158][159][160][161][162][163][164][165][166]. Another key signaling protein of mitochondrial retrograde signaling pathway, Akt kinase is induced in mtDNA depleted human mammary epithelial cells.…”

Section: Mitochondrial Retrograde Signaling In Emtmentioning

confidence: 99%

Epithelial To Mesenchymal Transition in Breast Cancer Metastasis: Mitochondria Take the Center Stage

Guha¹

2016

CBCM

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Epithelial to Mesenchymal Transition (EMT), a process involved in organogenesis and wound healing is now at the center stage of cancer metastasis. While most of the current research is focused on defects arising in the nuclear genome, the contribution of defects in mitochondria has remained under investigated. In the past decade, the association between mitochondrial genomic (mtDNA) and functional defects resulting in altered metabolism with tumor progression and poor outcome has become more evident. Here we review the contribution of mitochondria in epithelial-to-mesenchymal transition, particularly focusing on breast cancer. Our goal is to highlight the critical role that mitochondrial genome defects induced retrograde signaling play in driving cellular plasticity. We will further discuss the molecular intermediates of the retrograde signaling pathway, which can potentially be novel therapeutic targets in mitochondrial stress induced EMT.

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The splicing regulators Esrp1 and Esrp2 direct an epithelial splicing program essential for mammalian development

Cited by 128 publications

References 77 publications

Splicing-factor alterations in cancers

Splicing-factor alterations in cancers

Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

Epithelial To Mesenchymal Transition in Breast Cancer Metastasis: Mitochondria Take the Center Stage

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