Biology subjects

Czech Nicholson, B.

Publications and source records attributed to Czech Nicholson, B..

4 recordsLinked to original sources

bioRxiv2026

Targeting glucocorticoid signalling in dendritic cells for glioblastoma treatment

Glioblastoma (GBM) remains a devastating disease with few meaningful therapeutic advances over the past three decades. Dendritic cell (DC) vaccination is a promising immunotherapeutic strategy for GBM, but its efficacy is limited by the clinical use of dexamethasone to control cerebral oedema and associated symptoms. Here we show that steroid signalling is a central regulator of DC dysfunction in GBM. Through targeted metabolomics of primary GBM samples, we identified a steroid-rich tumour microenvironment in which dexamethasone is present at high levels. Across bulk and single-cell transcriptomic and epigenomic datasets, NR3C1 emerged as the dominant steroid receptor in GBM immune cells and was negatively associated with activated DC states. In patient-derived DCs, dexamethasone altered NR3C1 chromatin occupancy, induced broad transcriptional and chromatin remodelling, and suppressed co-stimulatory antigen-presentation and cytokine programmes. DC-specific deletion of Nr3c1 restricted syngeneic glioblastoma growth, enhanced DC activation, promoted cytotoxic CD8+ T cell responses and remodelled myeloid states in vivo. In GBM patient-derived DCs, pharmacological or non-viral CRISPR-mediated disruption of NR3C1 restored inflammatory, antigen presentation and T cell-stimulatory programmes, enhanced antigen-specific CD8+ T cell priming, and improved tumour lysate-loaded DC vaccination. Together, these findings identify glucocorticoid signalling as a key barrier to DC immunotherapy in GBM and establish NR3C1-targeted, steroid-resistant DCs as a potential therapeutic strategy.

immunology↗

bioRxiv2026

Lifestyles of Gypsy-family transposons shape their regulatory mechanisms

Transposable elements are a highly diverse group of selfish genomic elements, prevalent across the tree of life, whose uncontrolled propagation poses a threat to genome stability. Recent studies have explored the evolution of Drosophila melanogaster transposable elements, their co-evolution with the host genome, and mechanisms that regulate their activity. However, little is known about their cross-species evolutionary patterns. Long terminal repeat (LTR) retrotransposons are the most active group of transposable elements in Drosophila. They are broadly separated into retroelements, which are active in the germline, and insect endogenous retroviruses that express in the gonadal soma. Somatic elements are hypothesised to infect the germline through their acquisition of virus-derived proteins such as Envelope and sORF2, thus multiplying through successive generations. In this study, we curated the sequences of LTR retrotransposons in 249 drosophilid genomes, allowing us to study their evolution across these species and highlight their varying degrees of conservation. Furthermore, we reveal multiple instances of Envelope protein loss or inactivation that suggest shifts in the expression pattern of these transposons, likely accompanied by adopting different transcriptional control mechanisms. We contrast this with the evolutionary history of sORF2, which we found to be much more stable. Lastly, we examined variations in transposon LTR regions responsible for transcriptional regulation and use predictive modelling to suggest six transcription factors likely involved in their tissue-specific expression. Altogether, we reveal complex, interspecies evolutionary patterns of Gypsy-family LTR retrotransposons and highlight examples of their coevolution with their host genome.

genomics↗

bioRxiv2023

Promoters of germline transposon silencing genes evolve rapidly accompanied by diverging gene expression

BackgroundThe piRNA pathway in animal gonads functions as an RNA-based immune system, serving to silence transposable elements and prevent inheritance of novel invaders. In Drosophila, this pathway relies on three gonad-specific Argonaute proteins (Argonaute-3, Aubergine and Piwi) that associate with 23-28 nucleotide piRNAs, directing the silencing of transposon-derived transcripts. Transposons constitute a primary driver of genome evolution, yet the evolution of piRNA pathway factors has not received in-depth exploration. Specifically, channel nuclear pore proteins, which impact piRNA processing, exhibit regions of rapid evolution in their promoters. Consequently, the question arises whether such a mode of evolution is a general feature of transposon silencing pathways. ResultsBy employing genomic analysis of coding and promoter regions within genes that function in transposon silencing in Drosophila, we demonstrate that the promoters of germ cell-specific piRNA factors are undergoing rapid evolution. Our findings indicate that rapid promoter evolution is a common trait among piRNA factors engaged in germline silencing across insect species, potentially contributing to gene expression divergence in closely related taxa. Furthermore, we observe that the promoters of genes exclusively expressed in germ cells generally exhibit rapid evolution, with some divergence in gene expression. ConclusionOur results suggest that increased germline promoter evolution, in partnership with other factors, could contribute to transposon silencing and evolution of species through differential expression of genes driven by invading transposons.

evolutionary biology↗

bioRxiv2023

Unistrand piRNA clusters are an evolutionary conserved mechanism to suppress endogenous retroviruses across the Drosophila genus

The PIWI-interacting RNA (piRNA) pathway prevents endogenous genomic parasites, transposable elements, from damaging the genetic material of animal gonadal cells. Specific regions in the genome, called piRNA clusters, are thought to define each species piRNA repertoire and therefore its capacity to recognize and silence specific transposon families. The unistrand cluster flamenco (flam) is essential in the somatic compartment of the Drosophila ovary to restrict Gypsy-family transposons from infecting the neighbouring germ cells. Disruption of flam results in transposon derepression and sterility, yet it remains unknown whether this silencing mechanism is present more widely. Here, we systematically characterised 119 Drosophila species and identify five additional flam-like clusters separated by up to 45 million years. Small RNA-sequencing validated these as bona-fide unistrand piRNA clusters expressed in somatic cells of the ovary, where they selectively target transposons of the Gypsy family. Together, our study provides compelling evidence of a widely conserved transposon silencing mechanism that co-evolved with virus-like Gypsy-family transposons.

molecular biology↗