Biology subjects

Ghanegolmohammadi, F.

Publications and source records attributed to Ghanegolmohammadi, F..

4 recordsLinked to original sources

bioRxiv2025

Genes and Pathways Comprising the Human and Mouse ORFeomes Display Distinct Codon Bias Signatures that Can Regulate Protein Levels

Arginine, glutamic acid and selenocysteine based codon bias has been shown to regulate the translation of specific mRNAs for proteins that participate in stress responses, cell cycle and transcriptional regulation. Defining codon-bias in gene networks has the potential to identify other pathways under translational control. Here we have used computational methods to analyze the ORFeome of all unique human (19,711) and mouse (22,138) open-reading frames (ORFs) to characterize codon-usage and codon-bias in genes and biological processes. We show that ORFeome-wide clustering of gene-specific codon frequency data can be used to identify ontology-enriched biological processes and gene networks, with developmental and immunological programs well represented for both humans and mice. We developed codon over-use ontology mapping and hierarchical clustering to identify multi-codon bias signatures in human and mouse genes linked to signaling, development, mitochondria and metabolism, among others. The most distinct multi-codon bias signatures were identified in human genes linked to skin development and RNA metabolism, and in mouse genes linked to olfactory transduction and ribosome, highlighting species-specific pathways potentially regulated by translation. Extreme codon bias was identified in genes that included transcription factors and histone variants. We show that re-engineering extreme usage of C- or U-ending codons for aspartic acid, asparagine, histidine and tyrosine in the transcription factors CEBPB and MIER1, respectively, significantly regulates protein levels. Our study highlights that multi-codon bias signatures can be linked to specific biological pathways and that extreme codon bias with regulatory potential exists in transcription factors for immune response and development. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/636209v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@de9969org.highwire.dtl.DTLVardef@29e1dforg.highwire.dtl.DTLVardef@1abfebcorg.highwire.dtl.DTLVardef@e119b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Synonymous codon usage defines functional gene families

BackgroundThe degeneracy of the genetic code is increasingly recognized for roles in regulating translation rate, protein folding, and cell response. However, the functional genomics of codon usage patterns remains poorly defined. We previously showed that prokaryotic and eukaryotic cells respond to individual stresses by uniquely reprogramming the tRNA pool and the dozens of tRNA modifications comprising the tRNA epitranscriptome to cause selective translation of mRNAs from codon-biased genes. Here, we systematically defined distinct values of codon bias in the Saccharomyces cerevisiae genome by modeling isoacceptor codon distributions using a new statistical toolbox - analysis of synonymous codon signatures (ASCS). ResultsApplication of ASCS to the S. cerevisiae genome revealed linear relationships between patterns of codon bias and gene function using canonical correlation analysis. By mapping codon-biased open reading frames (ORFs) onto a functional network of Gene Ontology (GO) categories, we identified 115 gene families distinguished by unique codon usage signatures. The codon usage patterns were found to strongly predict functional clusters of genes, such as translational machinery, transcription, and metabolic processes. ConclusionsThe ASCS-derived model of codon usage patterns in S. cerevisiae reveals functional codon bias signatures and captures more biologically meaningful information when compared to other codon analytical approaches.

genetics↗

bioRxiv2024

Temporal dynamics and metagenomics of phosphorothioate epigenomes in the human gut microbiome

BackgroundEpigenetic regulation of gene expression and host defense is well established in microbial communities, with dozens of DNA modifications comprising the epigenomes of prokaryotes and bacteriophage. Phosphorothioation (PT) of DNA, in which a chemically-reactive sulfur atom replaces a non-bridging oxygen in the sugar-phosphate backbone, is catalyzed by dnd and ssp gene families widespread in bacteria and archaea. However, little is known about the role of PTs or other microbial epigenetic modifications in the human microbiome. Here we optimized and applied fecal DNA extraction, mass spectrometric, and metagenomics technologies to characterize the landscape and temporal dynamics of gut microbes possessing PT modifications. ResultsExploiting the nuclease-resistance of PTs, mass spectrometric analysis of limit digests of PT-containing DNA reveals PT dinucleotides as part of genomic consensus sequences, with 16 possible dinucleotide combinations. Analysis of mouse fecal DNA revealed a highly uniform spectrum of 11 PT dinucleotides in all littermates, with PTs estimated to occur in 5-10% of gut microbes. Though at similar levels, PT dinucleotides in fecal DNA from 11 healthy humans possessed signature combinations and levels of individual PTs. Comparison with a widely distributed microbial epigenetic mark, m6dA, suggested temporal dynamics consistent with expectations for gut microbial communities based on Taylors Power Law. Application of PT-seq for site-specific metagenomic analysis of PT-containing bacteria in one fecal donor revealed the larger consensus sequences for the PT dinucleotides in Bacteroidota, Firmicutes, Actinobacteria, and Proteobacteria, which differed from unbiased metagenomics and suggested that the abundance of PT-containing bacteria did not simply mirror the spectrum of gut bacteria. PT-seq further revealed low abundance PT sites not detected as dinucleotides by mass spectrometry, attesting to the complementarity of the technologies. ConclusionsThe results of our studies provide a benchmark for understanding the behavior of an abundant and chemically-reactive epigenetic mark in the human gut microbiome, with implications for inflammatory conditions of the gut.

microbiology↗

bioRxiv2022

Tissue- and sex-specific DNA damage tracks aging in rodents and humans

DNA damage causes genomic instability underlying many human diseases. Traditional approaches to DNA damage analysis provide minimal insights into the spectrum of disease-driving DNA lesions and the mechanisms causing imbalances in damage formation and repair. Here we used untargeted mass spectrometry-based adductomics1 to discover 114 putative DNA lesions and modifications consistently detected in humans and two independent analyses in rats, showing species-, tissue-, age-, and sex-biases. As evidence of methodologic rigor, 10 selected adductomic signals were structurally validated as epigenetic marks: 5-MdC, 5-HMdC, 5-FdC; DNA damage products: N2-CMdG, 1,N6 {varepsilon}-dA, 3,N4-{varepsilon}dC, M1dG, O6/N2-MdG, and 8-Oxo-dG; and established analytical artifacts: cyclobutane dimers of 2-deoxycytosine. With steady-state levels of putative DNA adducts integrating multiple cell types in each tissue, there was strong age-dependent variation for many putative adducts, including N2-CMdG, 5-HMdC, and 8-Oxo-dG in rats and 1,N6 {varepsilon}-dA in human heart, as well as sex biases for 67 putative adducts in rat tissues. These results demonstrate the potential of untargeted adductomic analysis for defining DNA adducts as disease determinants, assigning substrates to DNA repair pathways, discovering new metabolically-driven DNA lesions, and quantifying inter-individual variation in DNA damage and repair across populations.

biochemistry↗