Biology subjects

de Souza-Pinto, N. C.

Publications and source records attributed to de Souza-Pinto, N. C..

3 recordsLinked to original sources

bioRxiv2023

Combination of differential expression and co-expression network analyses identify novel conserved age-associated changes among different tissues

Transcriptomic changes occur with age, but the extent of their similarities across tissues is not clear. Previous studies have identified no similarity in age-modulated genes in different tissues. In this study, we sought to identify transcriptional changes with age across tissues using differential network analysis, with the premise that differential expression analysis alone is not capable of detecting all the changes in the transcriptional landscape that occur in tissues with age. Our results show major transcriptional alterations not detected by differential expression analysis that can be detected by differential connectivity analysis. Combining these two analyses, we detected genes changing across tissues, enriched in "RNA splicing" and "RNA processing", and highly connected in protein-protein interaction networks. Co-expression module analyses demonstrated that other genes with tissue-specific variations with age are enriched in pathways that combat accumulation of aberrant RNAs and proteins, which are caused by defective splicing. Additionally, tissues displayed a major reorganization of their genes connectivities with age, with most demonstrating convergent connectivity patterns. Our analyses identify genes and processes which transcriptional changes are conserved across tissues, demonstrating a central role for RNA splicing and processing genes and highlighting the importance of differential network analysis for understanding the ageing transcriptome.

bioinformatics↗

bioRxiv2023

Expression of DNA repair genes is modulated during differentiation of olfactory sensory neurons

Olfactory dysfunction is considered a biomarker of several pathological conditions, including age-associated neurodegenerations, glioblastoma and COVID-19. Olfactory sensory neurons (OSNs) are specialized neurons that detect odorants and send olfactory information to the brain through the olfactory bulb. To perform their function, they are in direct contact with the environment, where they are exposed to several environmental toxins such as atmospheric levels of O2 and volatile molecules. Nonetheless, very little is known about DNA damage levels and expression of DNA repair pathways in these cells. Here we measured nuclear and mitochondrial DNA damage in olfactory epithelium (OE) and compared with levels detected in olfactory bulb (OB) and temporal cortex (TC), as a non-olfactory related central nervous system region. Surprisingly, DNA damage was lower in OE and OB when compared with TC, both for nuclear and mitochondrial genomes. Accordingly, expression of representative genes for all excision repair pathways was detected in OSNs. Moreover, expression of most evaluated DNA repair genes was lower in mature versus OSN progenitors, suggesting that DNA repair is downregulated during differentiation. Analysis of single cell expression data confirmed that expression of the most differentially expressed DNA repair genes decreased from progenitor to mature OSNs. Finally, in situ hybridization data showed that APE1 mRNA levels are lower in the mature OSNs layer of the olfactory epithelium, closest to the nasal cavity lumen. Altogether, we show here that DNA repair pathways are relevant in protecting OSNs against DNA damage accumulation and that differentiation through the OE is accompanied by changes in the expression levels of DNA repair genes.

neuroscience↗

bioRxiv2022

The transcriptional repressor Opi1 modulates the DNA Damage Response by downregulation of inositol pyrophosphates in Saccharomyces cerevisiae

In budding yeast, the transcriptional repressor Opi1 regulates phospholipid biosynthesis by repressing expression of genes containing inositol-sensitive upstream activation sequences (UASINO). Upon genotoxic stress, cells activate the DNA Damage Response (DDR) to coordinate a complex network of signaling pathways aimed at preserving genomic integrity. Here, we reveal that Opi1 is important to modulate transcription in response to genotoxic stress. We find that cells lacking Opi1 exhibit hypersensitivity to genotoxins, along with a delayed G1 to S-phase transition and decreased gamma-H2A levels. Transcriptome analysis using RNA-seq reveals that Opi1 plays a central role in modulating essential biological processes during genotoxic stress induced by methyl methanesulfonate, including repression of phospholipid biosynthesis and transduction of mating signaling. Moreover, Opi1 induces sulfate assimilation and amino acid metabolic processes, such as arginine and histidine biosynthesis and glycine catabolism. Furthermore, we observe increased mitochondrial DNA instability in opi1{Delta} cells upon MMS treatment. Notably, we show that constitutive activation of the transcription factors Ino2-Ino4 is responsible for genotoxin sensitivity in Opi1-deficient cells, and the production of inositol pyrophosphates by Kcs1 counteracts Opi1 function specifically during MMS-induced genotoxic stress. Overall, our findings highlight Opi1 as a critical sensor of genotoxic stress in budding yeast, orchestrating gene expression to facilitate appropriate DNA damage response.

cell biology↗