VEGFA’s distal enhancer regulates its alternative splicing in CML

Dahan, Sara; Sharma, Aveksha; Cohen, Klil; Baker, Mai; Taqatqa, Nadeen; Bentata, Mercedes; Engal, Eden; Siam, Ahmad; Kay, Gillian; Drier, Yotam; Elias, Shlomo; Salton, Maayan

doi:10.1093/narcan/zcab029

Cited by 11 publications

(10 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The demethylation of vascular endothelial growth factor A (VEGFA) enhancer in CML promotes the overexpression of cancer signature genes. A study by Dahan showed that VEGFA+157 eRNA regulates its selective splicing, which affects CML cell proliferation by increasing RNAPII elongation via CCNT2 ( 161 ).…”

Section: Resultsmentioning

confidence: 99%

Inflammatory Immune-Associated eRNA: Mechanisms, Functions and Therapeutic Prospects

Wan

Meng

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

The rapid development of multiple high-throughput sequencing technologies has made it possible to explore the critical roles and mechanisms of functional enhancers and enhancer RNAs (eRNAs). The inflammatory immune response, as a fundamental pathological process in infectious diseases, cancers and immune disorders, coordinates the balance between the internal and external environment of the organism. It has been shown that both active enhancers and intranuclear eRNAs are preferentially expressed over inflammation-related genes in response to inflammatory stimuli, suggesting that enhancer transcription events and their products influence the expression and function of inflammatory genes. Therefore, in this review, we summarize and discuss the relevant inflammatory roles and regulatory mechanisms of eRNAs in inflammatory immune cells, non-inflammatory immune cells, inflammatory immune diseases and tumors, and explore the potential therapeutic effects of enhancer inhibitors affecting eRNA production for diseases with inflammatory immune responses.

show abstract

Section: Resultsmentioning

confidence: 99%

Inflammatory Immune-Associated eRNA: Mechanisms, Functions and Therapeutic Prospects

Wan

Meng

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…VEGF-A variants were differentially expressed in the organoids in hypoxia ( Figures 5A–C ), consistent with previous studies. ( Farina et al, 2020 ) VEGF-A189 was significantly upregulated in organoids cultured in hypoxia, which is associated with microvessel formation ( Li et al, 2004 ; Jagannathan et al, 2016 ) and enhanced migration of endothelial cells ( Dahan et al, 2021 ). Being positively charged in some domains, encoded for by exons 6a, 6b and 7, VEGF-A189 binds negatively charged extracellular matrix and heparan sulphate proteoglycans on cell surfaces, remaining spatially localized and becomes biologically active upon mobilization by heparinase.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Microvasculature Formation and Patterning in iPSC–Derived Kidney Organoids Cultured in Physiological Hypoxia

Schumacher

Roumans

Rademakers

et al. 2022

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

Stem cell–derived kidney organoids have been shown to self-organize from induced pluripotent stem cells into most important renal structures. However, the structures remain immature in culture and contain endothelial networks with low connectivity and limited organoid invasion. Furthermore, the nephrons lose their phenotype after approximately 25 days. To become applicable for future transplantation, further maturation in vitro is essential. Since kidneys in vivo develop in hypoxia, we studied the modulation of oxygen availability in culture. We hypothesized that introducing long-term culture at physiological hypoxia, rather than the normally applied non-physiological, hyperoxic 21% O2, could initiate angiogenesis, lead to enhanced growth factor expression and improve the endothelial patterning. We therefore cultured the kidney organoids at 7% O2 instead of 21% O2 for up to 25 days and evaluated nephrogenesis, growth factor expression such as VEGF-A and vascularization. Whole mount imaging revealed a homogenous morphology of the endothelial network with enhanced sprouting and interconnectivity when the kidney organoids were cultured in hypoxia. Three-dimensional vessel quantification confirmed that the hypoxic culture led to an increased average vessel length, likely due to the observed upregulation of VEGFA-189 and VEGFA-121, and downregulation of the antiangiogenic protein VEGF-A165b measured in hypoxia. This research indicates the importance of optimization of oxygen availability in organoid systems and the potential of hypoxic culture conditions in improving the vascularization of organoids.

show abstract

“…Our previous work has demonstrated the connection between enhancer activity and alternative splicing (42). The enhancer was demonstrated to promote transcription elongation kinetics to promote exon inclusion.…”

Section: Discussionmentioning

confidence: 99%

Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth

Sharma

Mistriel-Zerbib

Najar

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

T-cell acute lymphoblastic leukemia (T-ALL) protein 1 (TAL1) is a central transcription factor in hematopoiesis. The timing and level of TAL1 expression orchestrate the differentiation to specialized blood cells and its overexpression is a common cause of T-ALL. Here we studied the two protein isoforms of TAL1, short and long, that are generated by the use of alternative promoters as well as by alternative splicing. We analyzed the expression of each isoform by deleting an enhancer or insulator, or by opening chromatin at the enhancer location. Our results show that each enhancer promotes expression from a specific TAL1 promoter. Expression from a specific promoter gives rise to a unique 5’ UTR with differential regulation of translation. In addition, the enhancers regulate TAL1 exon 3 alternative splicing by altering the chromatin at its location. Furthermore, our results indicate that TAL1-short binds more strongly to TAL1 E-protein partners and functions as a stronger transcription factor than TAL1-long. Specifically TAL1-short has a unique transcription signature promoting apoptosis. Finally, when we expressed both isoforms in mice bone-marrow, we found that while overexpression of both isoforms prevents lymphoid differentiation, expression of TAL-short alone leads to hematopoietic stem cell exhaustion. Furthermore, we found that TAL1-short promoted erythropoiesis and reduced cell survival in the CML cell line K562. While TAL1 and its partners are considered promising therapeutic targets in the treatment of T-ALL, our results show that TAL1-short could act as a tumor suppressor and suggest that altering TAL1 isoform’s ratio could be a preferred therapeutic approach.

show abstract

VEGFA’s distal enhancer regulates its alternative splicing in CML

Cited by 11 publications

References 52 publications

Inflammatory Immune-Associated eRNA: Mechanisms, Functions and Therapeutic Prospects

Inflammatory Immune-Associated eRNA: Mechanisms, Functions and Therapeutic Prospects

Enhanced Microvasculature Formation and Patterning in iPSC–Derived Kidney Organoids Cultured in Physiological Hypoxia

Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth

Contact Info

Product

Resources

About