Biology subjects

Ogunsola, S.

Publications and source records attributed to Ogunsola, S..

4 recordsLinked to original sources

bioRxiv2025

A Mammalian Genomic Signature Shaped by Single Nucleotide Variants Controlling Transcriptome Integrity and Diversity

BackgroundMany functional features of mammalian genomic sequences remain poorly defined, especially how sequence motifs and genetic variants within non-coding regions (NCRs) regulate transcriptome integrity and diversity. We have shown that G-tracts unusually positioned between the polypyrimidine tract and 3' AG repress usage of the AG and are enriched at cryptic splice sites in cancer cells but their broader role across the extensive NCRs of mammalian genomes is unknown. ResultsHere, we identify a widely evolved genomic signature, G-tract-AG motifs consisting of guanine tracts closely upstream of AG dinucleotides, which is significantly associated with single-nucleotide variants (SNVs) identified in genome-wide association studies, particularly within NCRs. Approximately 9,000 such G-tracts within human genes are disrupted by variants of the cis-splicing quantitative trait loci in the Genotype-Tissue Expression project. Functionally, G-tracts repress splicing at the adjacent 3' AG, primarily by stalling the second transesterification step. Disruption of G-tracts by SNVs relieves this repression, enabling splicing and generating novel transcript isoforms. These G-tract-disrupting SNVs are in cis across the majority of protein-coding genes and are among thousands of rare variants causing genetic diseases. ConclusionsG-tract-AG signatures are widespread bipartite motifs with dual functions: G-tracts repress AG usage to safeguard transcriptome integrity, while SNV-induced disruption releases AGs for splicing to promote transcriptome diversity. Our findings provide mechanistic insights into the regulation of transcriptome integrity and diversity by a mammalian genomic signature, particularly for NCR SNVs associated with diverse traits and a new framework for their functional annotation.

genetics↗

bioRxiv2025

Specificity of Aberrant Exons in a Saturated Background of Differentially Expressed Exons

Determining the maximal specificity of aberrant exons from multifactorial disease tissues in a whole body background could provide insights into the exon origin as well as potential targets of diagnosis or therapy, but it remains a challenging task. For this purpose, we obtained a saturated list of differentially expressed exons (DEXs) from our independent reference human exome extracted from 56 normal tissues by DEXSeq. We found that the DEXs comprised the majority of the reference exome and that 99.4% of cancer-specific exons relative to paired normal tissues fell within the DEX list, consistent with the ectopic expression of the majority of aberrant exons. We then screened over seven thousand pathogenic single nucleotide variants (SNVs) in the TCGA and COSMIC databases by SpliceAI. The analysis identified over three hundreds of highly confident, mostly somatic SNV-specific splicing events and/or novel exonic fragments in five types of adenocarcinomas. Interestingly, these events are all associated with cis-acting mutations in tumor suppressor genes, particularly in TP53 with an antigenic novel peptide. This revelation of the DEX exome dominance and non-specificity of nearly all aberrant exons not only reshapes our understanding of the normal human exome by highlighting its mainly variable over constitutive exons, but also illuminates the path through cis-acting somatic and pathogenic SNVs to identify genuine cancer-specific exonic fragments that are absent in any normal tissues, beyond neo-exon junctions. This path holds promise for identifying novel peptide fragments for antigens in holistic cancer treatments including vaccination and immunotherapies.

cancer biology↗

bioRxiv2024

5-Aza-Cytidine Enhances Terminal Polyadenylation Site Usage for Full-Length Transcripts in Cells

As an inhibitor of DNA methyltransferases (DNMTs) and an anti-cancer drug, 5-aza-cytidine (5-azaC)s many effects on gene expression remains unclear. Here, we show that 5-azaC treatment of cultured GH3 pituitary tumour cells increases relative usage of genomic terminal exons (GTEs) across the transcriptome. This effect is largely achieved by shifting mRNA polyadenylation from proximal poly(A) sites to GTEs, which harbour a more optimal consensus motif of poly(A) signals. Consistent with this shift, 5-azaC upregulates the mRNA anti-termination factors Scaf4 and Scaf8 while downregulating the early termination enhancer E2f2. In MOLM-13 leukaemia cells, 5-azaC similarly promotes the production of full-length transcripts and regulates alternative polyadenylation factors, some of which in the same direction as observed in GH3 cells. Moreover, PCF11, a factor known to promote proximal poly(A) site usage, is upregulated in both cell lines, suggesting a homeostatic response by these cells to counteract transcript lengthening during 5-azaC treatment. Together, these findings uncover a previously unrecognized effect of 5-azaC on gene expression: directional promotion of terminal polyadenylation site usage, driving a transcriptome-wide switch from shortened to full-length mRNAs in tumour or cancer cells and consequently altering the alternative usage of multiple 3' exons.

cell biology↗

bioRxiv2024

Epigenetic Control of Adaptive or Homeostatic Splicing of Alternative Exons and Prolactin Gene Expression During Interval-Training Activities of Pituitary Cells

Interval-training activities induce adaptive cellular changes without altering their fundamental identity, but the precise underlying molecular mechanisms are not fully understood. In this study, we demonstrate that interval-training depolarization (ITD) of pituitary cells triggers distinct adaptive or homeostatic splicing responses of alternative exons. This occurs while preserving the steady-state expression of the Prolactin and other hormone genes. The nature of these splicing responses depends on the exons DNA methylation status, the methyl-C-binding protein MeCP2 and its associated CA-rich motif-binding hnRNP L. Interestingly, the steady expression of the Prolactin gene is also reliant on MeCP2, whose disruption during ITD leads to exacerbated overexpression and multi-exon aberrant splicing of the hormone gene transcripts, similar to the observed hyperprolactinemia or activity-dependent aberrant splicing in Rett Syndrome. Therefore, depending on how many times cells are stimulated, exons may exhibit different splicing responses to cell activities. During the ITD, epigenetic control is crucial for both adaptive or homeostatic splicing and the steady expression of the Prolactin hormone gene. Disruption in this regulation may have significant implications for the development of progressive diseases.

cell biology↗