Biology subjects

Mercuri, R. L. V.

Publications and source records attributed to Mercuri, R. L. V..

5 recordsLinked to original sources

bioRxiv2024

FREDDIE: A comprehensive tool for detecting exonization of retrotransposable elements in short and long RNA sequencing data

BackgroundTransposable elements (TEs) constitute a significant portion of mammalian genomes, accounting for about 50% of the total DNA. Intragenic TEs are of particular interest as they are co-transcribed with their host genes in pre-mRNA, potentially leading to the formation of novel chimeric transcripts and the exonization of TEs. The abundance of RNA sequencing data currently available offers a unique opportunity to explore transcriptomic variations. However, a significant limitation is the capability of existing computational tools. Here, we introduce FREDDIE, an innovative algorithm designed to detect the exonization of retrotransposable elements using RNA-seq data. FREDDIE can process short and long RNA sequencing data, assemble and quantify transcripts, evaluate coding potential, and identify protein domains in chimeric transcripts involving exonized TEs and retrocopies. ResultsTo demonstrate the efficacy of FREDDIE, we analyzed and validated TE exonization in two human cancer cell lines, K562 and U251. We have identified 322 chimeric transcripts, of which 126 were from K562, and 196 were from U251. Among these chimeric transcripts, there were 35 that showed similar exonization patterns and host genes. These transcripts involve protein-coding genes of the host and exonization of LINE-1 (L1), Alu elements, and retrocopies of coding genes. We have selected some candidates and validated them experimentally through RT-PCR. The validation rate for these candidates was 70%, later confirmed by long-read sequencing. Additionally, we applied FREDDIE to analyze TE exonization across 157 glioblastoma samples, identifying 1,010 chimeric transcripts. The majority of these transcripts involved the exonization of Alu elements (69.8%), followed by L1 (20.6%) and retrocopies (9.6%). Notably, we discovered a highly expressed L1 exonization within the ROS gene, resulting in a truncated open reading frame (ORF) with the deletion of two protein domains. ConclusionsFREDDIE is an efficient and user-friendly tool for identifying chimeric transcripts that involve exonization of intragenic TEs. Overall, FREDDIE enables comprehensive investigations into the contributions of TEs to transcriptome evolution, variation, and disease-associated abnormalities, and it operates effectively on standard computing systems. FREDDIE is publicly available: https://github.com/galantelab/freddie

bioinformatics↗

bioRxiv2023

RCPedia: A global resource for studying and exploring retrocopies in diverse species

MotivationGene retrocopies, or processed pseudogenes, arise from the reverse transcription and genomic insertion of processed mRNA transcripts. These elements have significantly contributed to genetic diversity and novelties throughout the evolution of many species. However, the study of retrocopies has been challenging, owing to the absence of comprehensive, complete, and user-friendly databases for diverse species. ResultsHere, we introduce an improved version of RCPedia, an integrative database meticulously designed for the study of retrocopies. RCPedia offers an extensive catalog of retrocopies identified across 44 species, which includes 13 primates, 4 rodents, 6 chiropterans, 12 other mammals, 4 birds, turtle, lizard, frog, zebrafish, and drosophila. The database offers the most complete compilation of retrocopies per species, accompanied by detailed genomic annotations, expression data, and links to other data portals. Furthermore, RCPedia features a streamlined representation of data and an efficient querying system, establishing it as an invaluable tool for researchers in the fields of genomics, evolutionary biology and transposable elements. In summary, RCPedia aims to enhance the investigation of retrocopies and their pivotal roles in shaping the genomic landscapes of diverse species. AvailabilityRCPedia is available at https://www.rcpediadb.org

bioinformatics↗

bioRxiv2023

TRANSPOSABLE ELEMENTS ALTER GENE EXPRESSION AND MAY IMPACT RESPONSE TO CISPLATIN THERAPY IN OVARIAN CANCER

Cisplatin is widely employed for cancer treatment; therefore, understanding resistance to this drug is critical for therapeutic practice. While studies have delved into differential gene expression in the context of cisplatin resistance, findings remain somewhat scant. In this study, we employed RNA-seq, ATAC-seq, and in-depth bioinformatics analyses to perform a detailed investigation of the cellular transcriptome, centering on Transposable Elements (TEs) expression in ovarian cancer cell lines both sensitive and resistant to cisplatin treatment. Our results reveal that cisplatin therapy alters the expression of protein-coding genes, but also key TEs, including LINE1, Alu, and endogenous retroviruses, in both cisplatin-sensitive and -resistant cell lines. By co-expressing with downstream genes or by creating chimeric transcripts with host genes at their insertion sites, these TEs seem to control the expression of protein-coding genes, including tumor-related genes. Notably, our model uncovers TEs influencing the expression of cancer genes and cancer pathways. Collectively, our findings indicate that TEs alterations associated with cisplatin treatment occur in critical cancer genes and cellular pathways synergically. In conclusion, this research highlights the importance of considering the entire spectrum of transcribed elements in the genome, especially TE expression, for a complete understanding of complex models like cancer response to treatment.

cancer biology↗

bioRxiv2023

Retro-miRs: Novel and functional miRNAs originated from mRNA retrotransposition

BackgroundReverse transcribed gene copies, or retrocopies, have emerged as a major source of evolutionary novelties. MicroRNAs (miRNAs) are small, highly conserved RNAs molecules among species that serve as key post-transcriptional regulators of gene expression. The birth and subsequent evolution of miRNAs have been addressed, but not fully. ResultsIn this study, we carried out a comprehensive investigation of miRNAs origination through retroduplicated mRNA sequences (retrocopies). We identified 17 retroduplicated miRNAs (retro-miRs) that emerged from mRNAs retrocopies. Four of these retro-miRs had de novo origination within retrocopied sequences, while 13 retro-miRNAs were located within exon regions and were duplicated along with their host mRNAs. We found that retro-miRs are primates specific, including 5 retro-miRs conserved among all primates and two human-specific retro-miRs. All of the retro-miRs were expressed and had predicted and experimentally validated target genes, with the exception of miR-10527. Notably, the target genes of retro-miRs are involved in key biological processes, such as metabolic processes, cell signaling and regulation of neurotransmitters in the central nervous system. Additionally, we found that these retro-miRs have a potential oncogenic role in cancer, targeting key cancer genes and being overexpressed in several cancer types, including Liver Hepatocellular Carcinoma and Stomach Adenocarcinoma. ConclusionOur findings demonstrate that mRNAs retrotransposition is a key mechanism for the generation of novel miRNAs (retro-miRs) in primates. These retro-miRs are expressed, conserved, have target genes with important cellular functions, and play roles in cancer.

genomics↗

bioRxiv2022

The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes

The exon junction complex (EJC) plays key roles throughout the lifespan of RNA and is particularly relevant in the nervous system. We investigated the roles of two EJC members, the paralogs MAGOH and MAGOHB, with respect to brain tumor development. High MAGOH/MAGOHB expression was observed in 14 tumor types; glioblastoma (GBM) showed the greatest difference compared to normal tissue. Increased MAGOH/MAGOHB expression was associated with poor prognosis in glioma patients, while knockdown of MAGOH/MAGOHB affected different cancer phenotypes. Reduced MAGOH/MAGOHB expression in GBM cells caused alterations in the splicing profile, including re-splicing and skipping of multiple exons. The binding profiles of EJC proteins indicated that exons affected by MAGOH/MAGOHB knockdown accumulated fewer complexes on average, providing a possible explanation for their sensitivity to MAGOH/MAGOHB knockdown. Transcripts (genes) showing alterations in the splicing profile are mainly implicated in cell division, cell cycle, splicing, and translation. We propose that high MAGOH/MAGOHB levels are required to safeguard the splicing of genes in high demand in scenarios requiring increased cell proliferation (brain development and GBM growth), ensuring efficient cell division, cell cycle regulation, and gene expression (splicing and translation). Since differentiated neuronal cells do not require increased MAGOH/MAGOHB expression, targeting these paralogs is a potential option for treating GBM.

cancer biology↗