Biology subjects

Fedorova, A. D.

Publications and source records attributed to Fedorova, A. D..

3 recordsLinked to original sources

bioRxiv2025

The earliest changes in the translatome upon human T cell activation

Stimulation of resting T cells triggers a rapid transition into an activated state, characterized by significant changes in phenotype, metabolism and secretory function. To explore the earliest responses, we examined transcriptional and translational changes in isolated human T cells within the first four hours post-stimulation. Polyclonal stimulation initially upregulates cytokine genes while downregulating certain transcription factors and regulators. Subsequently, selective mRNA translation occurs on 5-terminal oligopyrimidine (TOP) motif-containing mRNAs and ATF4, alongside global transcriptional reprogramming involving alternative transcription and splicing. Notably, both stimulated and unstimulated T cells undergo dynamic gene expression changes over time, reflecting adaptation to in vitro conditions and the loss of in vivo homeostatic signals. This includes heightened translation initiation stringency, particularly in non-stimulated cells. Thus, stress responses induced by standard T cell isolation protocols must be considered when investigating T cell signaling and activation.

immunology↗

bioRxiv2022

Thousands of human non-AUG extended proteoforms lack evidence of evolutionary selection among mammals

The synthesis of most proteins begins at AUG codons, yet a small number of non-AUG initiated proteoforms are also known. Here we used publicly available ribo-seq data with phylogenetic approaches to identify novel, previously uncharacterised non-AUG proteoforms. Unexpectedly we found that the number of non-AUG proteoforms identified with ribosome profiling data greatly exceeds those with strong phylogenetic support. We identified an association between proteoforms with alternative N-termini and multiple compartmentalisation of corresponding gene products. In dozens of genes N-terminal extensions encode localisation signals, including mitochondrial presequence and signal peptides. While the majority of non-AUG initiated proteoforms occur in addition to AUG initiated proteoforms, in few cases non-AUG appears to be the only start. This suggests that alternative compartmentalisation is not the only function of non-AUG initiation. Taking a conservative approach, we updated annotation of several genes in the latest GENCODE version in human and mouse where non-AUG initiated proteofoms are supported by both, ribosome profiling and phylogenetic evidence. Yet, the number of such extensions is likely much higher. Thousands of non-AUG proteoforms supported only by ribosome profiling suggest that they may evolve neutrally. Indeed, expression of some may not be consequential, i.e. when N-termini is processed or they have identical biochemical properties. Nonetheless they may contribute to immune response as antigen sources. It is also possible that some proteoforms accrued useful functions only recently and evolved under purifying selection in a narrow phylogenetic group. Thus, further characterisation is important for understanding their phenotypical and clinical significance.

genomics↗

bioRxiv2020

Enhanced C/EBPs binding to C>T mismatches facilitates fixation of CpG mutations

Knowledge of mechanisms responsible for mutagenesis of adult stem cells is crucial to track genomic alterations that may affect cell renovation and provoke malignant cell transformation. Mutations in regulatory regions are widely studied nowadays, though mostly in cancer. In this study, we decomposed the mutation signature of adult stem cells, mapped the corresponding mutations into transcription factor binding regions, and assessed mutation frequency in sequence motif occurrences. We found binding sites of C/EBP transcription factors strongly enriched with [C>T]G mutations within the core CG dinucleotide related to deamination of the methylated cytosine. This effect was also exhibited in related cancer samples. Structural modeling predicted enhanced CEBPB binding to the consensus sequence with the [C>T]G mismatch, which was then confirmed in the direct experiment. We propose that it is the enhanced binding of C/EBPs that shields C>T transitions from DNA repair and leads to selective accumulation of the [C>T]G mutations within binding sites.

genomics↗