Alternative splicing as a regulator of development and tissue identity

Baralle, Francisco E.; Giudice, Jimena

doi:10.1038/nrm.2017.27

Cited by 1,052 publications

(886 citation statements)

References 152 publications

(190 reference statements)

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“…Alternative splicing is a common post‐transcriptional modification that enables cells to increase protein diversity from a single copy of a gene by generation of unique coding transcripts or regulatory noncoding RNAs. These can be affected by changes in DNA methylation status and GC content at the intron–exon boundaries, ultimately affecting both splicing outcomes, alternative splicing networks and affecting writing and/or maintenance of epigenetic marks and changes in chromatin status (Francisco & Baralle, 2017; Shiran Naftelberg, Ast, & Kornblihtt, 2015). Transcripts associated with chromatin remodelling were significantly affected by the perfusion status in our cohort and included polycomb group genes (BMI1, SUZ12, TRIM27); chromobox/HP1 homologs (CBX4, CBX8); bromodomain proteins (BRD2, WDR11); ING family members (ING1, INg2, ING4) and PHF21B.…”

Section: Resultsmentioning

confidence: 99%

A molecular signature for delayed graft function

et al. 2018

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Chronic kidney disease and associated comorbidities (diabetes, cardiovascular diseases) manifest with an accelerated ageing phenotype, leading ultimately to organ failure and renal replacement therapy. This process can be modulated by epigenetic and environmental factors which promote loss of physiological function and resilience to stress earlier, linking biological age with adverse outcomes post‐transplantation including delayed graft function (DGF). The molecular features underpinning this have yet to be fully elucidated. We have determined a molecular signature for loss of resilience and impaired physiological function, via a synchronous genome, transcriptome and proteome snapshot, using human renal allografts as a source of healthy tissue as an in vivo model of ageing in humans. This comprises 42 specific transcripts, related through IFNγ signalling, which in allografts displaying clinically impaired physiological function (DGF) exhibited a greater magnitude of change in transcriptional amplitude and elevated expression of noncoding RNAs and pseudogenes, consistent with increased allostatic load. This was accompanied by increased DNA methylation within the promoter and intragenic regions of the DGF panel in preperfusion allografts with immediate graft function. Pathway analysis indicated that an inability to sufficiently resolve inflammatory responses was enabled by decreased resilience to stress and resulted in impaired physiological function in biologically older allografts. Cross‐comparison with publically available data sets for renal pathologies identified significant transcriptional commonality for over 20 DGF transcripts. Our data are clinically relevant and important, as they provide a clear molecular signature for the burden of “wear and tear” within the kidney and thus age‐related physiological capability and resilience.

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Section: Resultsmentioning

confidence: 99%

A molecular signature for delayed graft function

et al. 2018

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“…An increasing number of evidence suggests that AS contributes to cell differentiation, lineage determination, tissue-identity acquisition and maintenance and organ development 23. Although the splice site is essential to assemble a functional spliceosome, the auxiliary elements to regulate splicing events are also indispensable.…”

Section: Discussionmentioning

confidence: 99%

SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer

Wan

Shen

et al. 2017

Gut

138

146

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“…[2][3][4] Among patients with HNSCC, human papillomavirus (HPV)negative HNSCC has demonstrated a worse response to treatment and a poorer prognosis compared with HPV-positive HNSCC. 7,8 Given the importance of ASEs in regulating gene expression, the role of alternative splicing in tumorigenesis has attracted considerable interest, 9,10 and many cancer-related genes are considered to have functional diversity due to alternative splicing. In humans, it is estimated that >95% of multiexonic genes are alternatively spliced, which largely expands the complexity and diversity of human genes.…”

Section: Introductionmentioning

confidence: 99%

A novel splice variant of LOXL2 promotes progression of human papillomavirus–negative head and neck squamous cell carcinoma

Liu

Guo

Sakai

et al. 2019

Cancer

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BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed cancers worldwide. LOXlike (LOXL) 2 (LOXL2) demonstrates alternative splicing events in patients with human papillomavirus (HPV)-negative HNSCC. The current study explored the role of a dominant LOXL2 variant in HPV-negative HNSCC. METHODS: Expression of the LOXL2 variant was analyzed using The Cancer Genome Atlas cohorts and validated using quantitative reverse transcriptase-polymerase chain reaction in a separate primary tumor set. The authors defined the effect of LOXL2 splice variants in assays for cell proliferation using a cell viability assay and colony formation assay. Cell migration and invasion were examined using a cell scratch assay and transwell cell migration and invasion assay in LOXL2 splice variant gain and loss of expression cells. Western blot analysis and gene set enrichment analysis were used to explore the potential mechanism of the LOXL2 splice variant in HPV-negative HNSCC. RESULTS: Expression of a novel LOXL2 variant was found to be upregulated in The Cancer Genome Atlas HPV-negative HNSCC, and confirmed in the separate primary tumor validation set. Analyses of loss and gain of function demonstrated that this LOXL2 variant enhanced proliferation, migration, and invasion in HPV-negative HNSCC cells and activated the FAK/AKT pathway. A total of 837 upregulated and 820 downregulated genes and 526 upregulated and 124 downregulated pathways associated with LOXL2 variant expression were identified using gene set enrichment analysis, which helped in developing a better understanding of the networks activated by this LOXL2 variant in patients with HPV-negative HNSCC. CONCLUSIONS: The novel LOXL2 variant can promote the progression of HPV-negative HNSCC, in part through FAK/AKT pathway activation, which may provide a new potential therapeutic target among patients with HPV-negative HNSCC. Cancer 2020;126:737-748.

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Alternative splicing as a regulator of development and tissue identity

Cited by 1,052 publications

References 152 publications

A molecular signature for delayed graft function

A molecular signature for delayed graft function

SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer

A novel splice variant of LOXL2 promotes progression of human papillomavirus–negative head and neck squamous cell carcinoma

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