Gene Expression Profiles Controlled by the Alternative Splicing Factor Nova2 in Endothelial Cells

Belloni, Elisa; Matteo, Anna Di; Pradella, Davide; Vacca, Margherita; Wyatt, Christopher D R; Alfieri, Roberta; Maffia, Antonio; Sabbioneda, Simone; Ghigna, Claudia

doi:10.3390/cells8121498

Cited by 12 publications

(10 citation statements)

References 96 publications

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“…By regulating splicing, NOVA2 determines vascular morphogenesis and endothelial biology 22 . Inspecting the knowledge associated with the listed genes by OT showed that many of the genes (Table 3) contributed to the genetic basis of physical measurements (e.g., BMI), brain and eye measurements.…”

Section: Gene-based Associations Using Skat and Pwas Analysesmentioning

confidence: 99%

The genetics of idiopathic intracranial hypertension (IIH): Integration of population studies and clinical data

Zucker,

Kovalerchik,

Davidovich

et al. 2023

Preprint

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Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure without a known cause. It mainly affects overweight, reproductive-age women, and its genetic basis remains unknown. Previous GWAS failed to find significant associations. To address this, we analyzed a cohort of 173 IIH and papilledema (PAP) patients from the UK Biobank (UKB) using various genetic association methods. We activate a GWAS that covers only coding regions of genes for better interpretability. We also employed the complementary methods of SKAT and PWAS, which aggregate variants to determine gene-based association. We report on 10 overlapping genes by two methods, with FOXF1 and RGCC identified by all three methods. In a separate GWAS on a Finnish cohort, a rare variant in the LRRFIP1 gene was associated with IIH. Comparing findings from the Finnish, IIH, and PAP cohorts, we discovered the SHANK2 gene as a shared genetic factor. Genes related to the choroid plexus epithelium cluster (MAPK15, DCDC1, DNAH5, and SLC28A3) were found to be enriched, suggesting a role for microtubule cilia regulation in IIH etiology. Importantly, many GWAS-associated coding variants were predicted to be deleterious and rare in healthy populations. Comorbidities associated with IIH and PAP include pain, migraines, and psychological and mental disorders. This study highlights the strength of an integrative genetic approach, combining functional and clinical knowledge, to better understand IIH etiology. By identifying potential genetic factors and their biological relevance, this research provides insights into IIH's causes and paves the way for further investigation and potential therapeutic interventions.

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Section: Gene-based Associations Using Skat and Pwas Analysesmentioning

confidence: 99%

The genetics of idiopathic intracranial hypertension (IIH): Integration of population studies and clinical data

Zucker,

Kovalerchik,

Davidovich

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Consistently, nova2 zebrafish mutants present many vascular defects [ 184 ]. NOVA2 modulates AS of genes involved in EC cytoskeleton organization and cell-cell adhesion, as well as the transcription factors PPAR-γ and E2F Dimerization Partner 2 (Tfdp2) [ 187 ]. Very recently NOVA2 was shown to modulate AS of components of Mapk/Erk pathway during lymphatic EC specification [ 186 ].…”

Section: Main Textmentioning

confidence: 99%

“…A number of EC-specific RBFOX2 splicing targets encode for ECM components or factors involved in cell adhesion, cell cycle, cytoskeletal remodeling and immune response [ 31 ]. Similar to NOVA2 [ 184 , 187 ], RBFOX2 also regulates the abundance of mRNAs transcribed from genes that belong to the same GO categories [ 31 ], suggesting that similar biological processes could be modulated by RBFOX2 in ECs through both transcriptional and post-transcriptional mechanisms.…”

Section: Main Textmentioning

confidence: 99%

Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis

Matteo

Belloni

Pradella

et al. 2020

J Exp Clin Cancer Res

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Alternative splicing (AS) is a pervasive molecular process generating multiple protein isoforms, from a single gene. It plays fundamental roles during development, differentiation and maintenance of tissue homeostasis, while aberrant AS is considered a hallmark of multiple diseases, including cancer. Cancer-restricted AS isoforms represent either predictive biomarkers for diagnosis/prognosis or targets for anti-cancer therapies. Here, we discuss the contribution of AS regulation in cancer angiogenesis, a complex process supporting disease development and progression. We consider AS programs acting in a specific and non-redundant manner to influence morphological and functional changes involved in cancer angiogenesis. In particular, we describe relevant AS variants or splicing regulators controlling either secreted or membrane-bound angiogenic factors, which may represent attractive targets for therapeutic interventions in human cancer.

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“…The current knowledge on the role of AS during vascular development and angiogenesis is still limited. The Neuro-oncological ventral antigen 2 (NOVA2) is a tissue-restricted SRF expressed by ECs of the blood vessels where it orchestrates vascular morphogenesis 27 – 29 and lymphatic EC specification 30 . NOVA2 is involved in multiple diseases.…”

Section: Introductionmentioning

confidence: 99%

A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis

et al. 2021

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The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B’s necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis.

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Gene Expression Profiles Controlled by the Alternative Splicing Factor Nova2 in Endothelial Cells

Cited by 12 publications

References 96 publications

The genetics of idiopathic intracranial hypertension (IIH): Integration of population studies and clinical data

The genetics of idiopathic intracranial hypertension (IIH): Integration of population studies and clinical data

Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis

A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis

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