Regulation of alternative splicing by p300-mediated acetylation of splicing factors

Siam, Ahmad; Baker, Mai; Amit, Leah; Regev, Gal; Rabner, Alona; Najar, Rauf Ahmad; Bentata, Mercedes; Dahan, Sara; Cohen, Klil; Araten, Sarah; Nevo, Yuval; Kay, Gillian; Mandel-Gutfreund, Yael; Salton, Maayan

doi:10.1261/rna.069856.118

Cited by 40 publications

(32 citation statements)

References 66 publications

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“…Five out of the six splicing factors have been shown before to be overexpressed in breast cancer: HNRNPA1 [ 33 ], HNRNPA2B1 [ 34 , 35 ], HNRNPK [ 36 , 37 ], PTBP1 [ 38 , 39 ] and SRSF6 [ 40 , 41 , 42 ]. For normalization we chose PPIA, which is routinely used as an endogenous control in real-time experiments [ 43 ] and we have found it to be highly abundant relative to the other genes sequenced, with a number of 197 reads in cell-free RNA from saliva ( Figure 1 d). For this reason, we used it here as our normalizer to measure the relative abundance of the splicing factors.…”

Section: Resultsmentioning

confidence: 99%

Splicing Factor Transcript Abundance in Saliva as a Diagnostic Tool for Breast Cancer

Bentata

Morgenstern

Nevo

et al. 2020

Genes

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Breast cancer is the second leading cause of death in women above 60 years in the US. Screening mammography is recommended for women above 50 years; however, 22% of breast cancer cases are diagnosed in women below this age. We set out to develop a test based on the detection of cell-free RNA from saliva. To this end, we sequenced RNA from a pool of ten women. The 1254 transcripts identified were enriched for genes with an annotation of alternative pre-mRNA splicing. Pre-mRNA splicing is a tightly regulated process and its misregulation in cancer cells promotes the formation of cancer-driving isoforms. For these reasons, we chose to focus on splicing factors as biomarkers for the early detection of breast cancer. We found that the level of the splicing factors is unique to each woman and consistent in the same woman at different time points. Next, we extracted RNA from 36 healthy subjects and 31 breast cancer patients. Recording the mRNA level of seven splicing factors in these samples demonstrated that the combination of all these factors is different in the two groups (p value = 0.005). Our results demonstrate a differential abundance of splicing factor mRNA in the saliva of breast cancer patients.

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Section: Resultsmentioning

confidence: 99%

Splicing Factor Transcript Abundance in Saliva as a Diagnostic Tool for Breast Cancer

Bentata

Morgenstern

Nevo

et al. 2020

Genes

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“…The mechanism and outcomes of alternative splicing of individual transcripts are well understood [1]. Some studies find that AS regulation is independent or partially independent of transcriptional regulation[19] and implement great function at the early stage of heat response[19,20], useful for future heat sensing and signaling studies [1]. Our new findings of AS provided important information for facilitating castor genome annotation and fully characterization of castor transcriptome.…”

Section: Discussionmentioning

confidence: 96%

A comparative transcriptional landscape of two castor cultivars obtained by single-molecule sequencing comparative analysis

Zhou

Guo-li

et al. 2020

Preprint

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Background and Objectives Castor ( Ricinus communis L.) is an important non-edible oilseed crop. Lm type female strains and normal amphiprotic strains are important castor cultivars, and are mainly different in inflorescence structures and leaf shapes. To better understand the mechanisums underling these differences at the molecular level, we performed comparative transcriptional analysis. Materials and Methods Full-length transcriptome sequencing and short-read RNA sequencing were employed. Results A total of 76,068 and 44,223 non-redundant transcripts were obtained from high-quality transcripts of Lm type female strains and normal amphiprotic strains, respectively. In Lm female strain and normal amphiprotic strains 51,613 and 20,152 alternative splicing events were found, respectively. There were 13,239 transcription factors identified from the full-length transcriptomes. Comparative analysis showed great different gene expression of common and unique transcription factors between the two cultivars. Meanwhile, functional analysis of isoform was conducted. Full-length sequences were used as a reference genome, and short-read RNA sequencing analysis was performed to conduct differential gene analysis. Furthermore, the function of DEGs were performed to annotation analysis. Conclusions The results revealed considerable difference and expression diversity between two cultivars, well beyond what was reported in previous studies, likely reflecting the differences in architecture between these two cultivars.

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“…Our previous work connected promoter activity to alternative splicing by the acetyltransferase p300. Binding of p300 at the promoter region acetylates not only histones at this region, but also splicing factors so regulating alternative splicing of the specific gene [49].…”

Section: Discussionmentioning

confidence: 99%

VEGFA’s distal enhancer regulates its alternative splicing in CML

Dahan

Cohen

Dentata

et al. 2021

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Enhancer demethylation in leukemia and lymphoma was shown to lead to overexpression of genes which promote cancer characteristics. The vascular endothelial growth factor A (VEGFA) enhancer, located 157 Kb downstream of its promoter, is demethylated in chronic myeloid leukemia (CML). VEGFA has several alternative splicing isoforms with different roles in vascularization and cancer progression. Since transcription and splicing are coupled in space and time, we hypothesized that the VEGFA enhancer can also regulate the gene’s alternative splicing to contribute to the pathology of CML. Our results show that mutating the VEGFA +157 enhancer promotes exclusion of exons 6b and 7 and activating the enhancer by tethering a chromatin activator has the opposite effect. In line with these results, CML patients display high enhancer activity and inclusion of VEGFA exons 6b and 7. To search for a key protein connecting transcription with alternative splicing, we analyzed 161 chromatin immunoprecipitation (ChIP)-seq experiments for DNA binding proteins and found that PML and CCNT2 bind VEGFA’s promoter and enhancer. CCNT2 is a positive regulator of RNA polymerase II (RNAPII) transcription elongation and indeed its silencing promotes exclusion of exons 6b and 7. Slowing down RNAPII elongation promotes exclusion of exons 6b and 7. Thus our results suggest that VEGFA’s +157 enhancer regulates its alternative splicing by increasing RNAPII elongation rate via CCNT2. Our work demonstrates the importance of the interplay between transcription and alternative splicing.

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Regulation of alternative splicing by p300-mediated acetylation of splicing factors

Cited by 40 publications

References 66 publications

Splicing Factor Transcript Abundance in Saliva as a Diagnostic Tool for Breast Cancer

Splicing Factor Transcript Abundance in Saliva as a Diagnostic Tool for Breast Cancer

A comparative transcriptional landscape of two castor cultivars obtained by single-molecule sequencing comparative analysis

VEGFA’s distal enhancer regulates its alternative splicing in CML

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