Biology subjects

Davidson, I.

Publications and source records attributed to Davidson, I..

14 recordsLinked to original sources

bioRxiv2026

Divergent coronaviruses discovered in the virome of lamprey with reddening syndrome

Lamprey reddening syndrome (LRS) is an emerging disease affecting pouched lamprey (Geotria australis; kanakana/piharau), a culturally and ecologically significant species in Aotearoa New Zealand. Characterised by skin haemorrhaging and elevated mortality, the aetiology of LRS has remained unresolved despite previous investigations. We used a metatranscriptomic approach to characterise viral communities in 28 lamprey from New Zealand and Tasmania, Australia, comparing diseased and presumably healthy individuals. This analysis revealed eight fish-infecting RNA viruses, seven of which were novel, including two highly divergent coronaviruses. One of these coronaviruses possessed a bi-segmented genome structure, and three lamprey were co-infected with both coronaviruses. While these coronaviruses were detected in both healthy and diseased individuals, lamprey with reddening exhibited markedly higher viral abundance, driven by elevated RNA transcripts of both viruses. This pattern suggests that increased coronavirus replication in diseased individuals may be influenced by host stress to environmental factors or co-infection with other pathogens, rather than acting as a sole causative agent of disease. Beyond identifying candidate viral associations, this study expands the known virosphere of an ancient vertebrate lineage and demonstrates the utility of genomics-informed diagnostics for investigating disease in threatened wildlife.

microbiology↗

bioRxiv2025

Interaction of lncRNA LENT with DHX36 regulates translation and suppresses autophagy in melanoma.

The melanocyte lineage determining Microphthalmia-associated transcription factor (MITF) drives proliferation and survival of melanocytic melanoma cells through regulation of both coding genes and long non-coding RNAs (LncRNAs). Here we characterize LINC00520 (hereafter called LncRNA ENhancer of Translation, LENT) regulated by MITF and strongly expressed in melanocytic melanoma cells. LENT is essential for proliferation and survival of cultured melanocytic melanoma cells and xenograft tumours. LENT interacts with the G4 quadruplex resolvase DHX36 and both associate with the ribosome in the 80S and light polysome fractions. LENT modulates DHX36 association with a collection of mRNAs regulating their engagement with polysomes and fine-tuning their subsequent translation. These mRNAs encode proteins involved in endoplasmic reticulum (ER) and mitochondrial homeostasis as well as autophagy. Consequently, LENT silencing leads to extensive autophagy and mitophagy, compromised oxidative metabolic capacity accompanied by an accumulation and mis-localization of mitochondrial proteins leading to proteotoxic stress and apoptosis. The LENT-DHX36 axis therefore fine-tunes translation of proteins involved in ER and mitochondrial homeostasis suppressing autophagy and promoting survival and proliferation of melanoma cells.

cancer biology↗

bioRxiv2024

TFE3 fusion proteins drive oxidative metabolism, ferroptosis resistance and general RNA synthesis in translocation renal cell carcinoma

The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterised. Here, we integrated loss and gain of function experiments with multi-omics analyses in tRCC cell lines and patient tumors. High nuclear accumulation of NONO-TFE3 or PRCC-TFE3 fusion proteins promotes their broad binding across the genome at H3K27ac-marked active chromatin, engaging a core set of M/E-box-containing regulatory elements to activate specific gene expression programs as well as promiscuous binding to active promoters to stimulate mRNA synthesis. Within the core program, TFE3 fusions directly regulate genes involved in ferroptosis resistance and oxidative phosphorylation metabolism (OxPhos) increasing functional OxPhos levels. Consequently, human tRCC tumors display high OxPhos scores that persist during their epithelial to mesenchymal transition (EMT). We further show that tRCC tumour aggressiveness is related to their EMT and their associated enrichment in myofibroblast cancer-associated fibroblasts (myCAFs) that are both hallmarks of poor prognostic outcomes. We define tRCC as a novel metabolic subtype of renal cancer and provide unique insights into how broad genomic binding of TFE3 fusion proteins regulates OxPhos and ferroptosis resistance and more generally stimulates RNA synthesis. SynopsisDefining the gene expression programs regulated by TFE3 fusion proteins in translocation renal cell carcinoma. TFE3 fusion proteins promote expression of oxidative metabolism genes and oxidative metabolism in tRCC. TFE3 fusion proteins regulate glutathione metabolism and ferroptosis resistance in tRCC. TFE3 fusion proteins bind broadly at active promoters and stimulate RNA synthesis in tRCC. Epithelial-to-mesenchymal transition in tRCC is accompanied by enrichment in myofibroblastic cancer-associated-fibroblasts and poor patient outcome. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/620047v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@b9dcb6org.highwire.dtl.DTLVardef@495f42org.highwire.dtl.DTLVardef@10d1770org.highwire.dtl.DTLVardef@7df40c_HPS_FORMAT_FIGEXP M_FIG C_FIG The paper explained. Problem.Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney cancer characterised by genetic translocation events frequently involving transcription factor TFE3 or more rarely TFEB. While the resulting fusion proteins are considered as the oncogenic drivers, their mechanism of action remains poorly understood. Results.By integrative multi-omics analyses in tRCC cell lines and patient tumors together with loss and gain of function experiments, we found broad binding of TFE3-fusion proteins at active promoters and identified a core set of target genes involved in multiple pathways, including oxidative metabolism (OxPhos) and ferroptosis. Consequently, tRCC cell lines displayed higher functional OxPhos levels and patient tumours displayed elevated OxPhos scores and ferroptosis resistance gene expression. Analyses of tRCC patient transcriptome data further revealed that mesenchymal tRCC tumours are enriched in myofibroblastic cancer associated fibroblasts that are hallmarks of poor prognostic outcome. ImpactThis study advances understanding of the molecular mechanisms underlying oncogenic transformation by TFE3 fusion proteins by defining a core program of gene expression and key features of tumour cells and their microenvironment that negatively impact patient outcome. Our integrative multi-omics and functional analyses reveal how extensive genomic binding of TFE3 fusion proteins drives high levels of oxidative metabolism, ferroptosis resistance and general RNA synthesis.

cancer biology↗

bioRxiv2024

NIPBL and STAG1 enable loop extrusion by providing differential DNA-cohesin affinity

DNA loop extrusion by cohesin has emerged as a critical pathway for chromosome organization. In vitro single-molecule experiments indicate that loop extrusion requires the assembly of an heteropentameric complex consisting of the SMC1/SMC3 heterodimer, STAG1, NIPBL and the kleisin SCC1. The multimeric nature of this complex and regulatoin of its dynamic DNA interactions that are modulated by ATP binding-hydrolysis cycles make it challenging to reveal the molecular mechanism of loop extrusion. Here, we use mass photometry to quantify the key interactions responsible for cohesin assembly, DNA binding, and their modulation by ATP binding and hydrolysis. We find that STAG1 binds tightly to the trimeric complex formed by the SMC1/SMC3 heterodimer and SCC1, creating a DNA binding site whose strength is modulated by the presence of ATP. NIPBL binds strongly to both DNA and the STAG1-tetramer, enabling assembly of the holoenzyme in the absence of DNA or ATP. Taken together, these results suggest that NIPBL acts as a DNA anchor, while a dynamic STAG1-Trimer binding site drives DNA loop formation.

biophysics↗

bioRxiv2023

SMC motor proteins extrude DNA asymmetrically and contain a direction switch

Structural Maintenance of Chromosomes (SMC) complexes organize the genome via DNA loop extrusion. While some SMCs were reported to do so symmetrically, reeling DNA from both sides into the extruded DNA loop simultaneously, others perform loop extrusion asymmetrically toward one direction only. The mechanism underlying this variability remains unclear. Here, we examine the directionality of DNA loop extrusion by SMCs using in vitro single-molecule experiments. We find that cohesin and SMC5/6 do not reel in DNA from both sides, as reported before, but instead extrude DNA asymmetrically, while the direction can switch over time. Asymmetric DNA loop extrusion thus is the shared mechanism across all eukaryotic SMC complexes. For cohesin, direction switches strongly correlate with the turnover of the subunit NIPBL, during which DNA strand switching may occur. STAG1 stabilizes NIPBL on cohesin, preventing NIPBL turnover and direction switches. The findings reveal that SMCs, surprisingly, contain a direction switch subunit. HighlightsO_LIAll eukaryotic SMC complexes extrude DNA asymmetrically. C_LIO_LIApparent symmetric loop extrusion is the result of frequent direction switches. C_LIO_LIn human cohesin, loop-extrusion direction changes require exchange of NIPBL. C_LIO_LISTAG1 stabilizes NIPBL on human cohesin. C_LI

molecular biology↗

bioRxiv2023

Super-enhancer driven expression of BAHCC1 promotes melanomacell proliferation and genome stability

Super enhancers (SE) are stretches of active enhancers ensuring high expression levels of key genes associated with cell function and survival. The identification of cancer-specific SE-driven genes and their functional characterization may prove to be a powerful means for the development of innovative therapeutic strategies. By performing epigenomic profiling in patient-derived short-term melanoma cultures, we identify a SE promoting the specific expression of BAHCC1 in a broad panel of cutaneous and uveal melanoma cells. BAHCC1 is highly expressed in metastatic melanoma, correlates with decreased patient survival and is required for tumor growth. Integrative genomics analyses reveal that BAHCC1 is a transcriptional regulator controlling expression of a subset of E2F/KLF-dependent cell cycle and DNA repair genes. BAHCC1 associates with BRG1-containing remodeling complexes at the promoters of these genes. In agreement, BAHCC1 silencing leads to decreased cell proliferation and delay in DNA repair. Consequently, BAHCC1 deficiency cooperates with PARP inhibition to induce melanoma cell death. Our study identifies a novel SE-driven gene expressed in cutaneous and uveal melanoma and demonstrates how its inhibition can be exploited as a therapeutic target, alone or in combination with DNA damage-inducing agents.

cancer biology↗

bioRxiv2022

The E-cadherin-ESR1-GRPR axis defines a sex-specific metastatic pathway in melanoma

Although tremendous progress has been made in understanding the mechanisms leading to cancer, those governing metastases are still poorly understood. E-cadherin (Ecad) is a cell-cell adhesion molecule essential for tissue homeostasis, and its loss often correlates with the dissemination of human cancers. However, whether and how the loss of Ecad triggers the full metastatic program is largely unknown. Here, we show that the loss of Ecad promotes melanoma lung metastases in females. The loss of Ecad, after the induction of estrogen receptor (ER) expression, activates gastrin-releasing peptide receptor (GRPR) expression. GRPR promotes cellular processes essential for metastasis formation through G{square}q and YAP1 signaling and its pharmacological inhibition reduces metastasis in vivo. This study reveals an Ecad-ER-GRPR metastatic sex dimorphism axis in melanoma that is conserved in human breast cancer and provides proof of concept that the G-coupled receptor GRPR is a therapeutic target for metastasis.

cancer biology↗

bioRxiv2022

Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks

Muscle-invasive bladder cancer (BLCA) is an aggressive disease. Consensus BLCA transcriptomic subtypes have been proposed, with two major Luminal and Basal subgroups, presenting distinct molecular and clinical characteristics. However, how these distinct subtypes are regulated remains unclear. We hypothesized that epigenetic activation of distinct super-enhancers could drive the transcriptional programs of BLCA subtypes. Through integrated RNA-sequencing and epigenomic profiling of histone marks in primary tumours, cancer cell lines, and normal human urothelia, we established the first integrated epigenetic map of BLCA and demonstrated the link between subtype and epigenetic control. We identified the repertoire of activated super-enhancers and highlighted Basal, Luminal and Normal-associated SEs. We revealed the super-enhancer-regulated networks of candidate master transcription factors for Luminal and Basal subgroups including FOXA1 and ZBED2 respectively. FOXA1 CRISPR-Cas9 mutation triggered a shift from Luminal to Basal phenotype, confirming its role in Luminal identity regulation and induced ZBED2 overexpression. In parallel, we showed that both FOXA1 and ZBED2 play concordant roles in preventing inflammatory response in cancer cells through STAT2 inhibition. Our study furthers the understanding of epigenetic regulation of muscle-invasive BLCA and identifies a co-regulated network of super-enhancers and associated transcription factors providing potential targets for the treatment of this aggressive disease.

cancer biology↗

bioRxiv2021

Integrative genomics uncover mechanisms of renal medullary carcinoma transformation, microenvironment landscape and therapeutic vulnerabilities.

Renal medullary carcinoma (RMC) is an aggressive desmoplastic tumour driven by bi-allelic loss of SMARCB1, however the cell-of-origin, the oncogenic mechanism and the features of its microenvironment remain poorly understood. Using single-cell and multi-region sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into at least three RMC cell states along an epithelial-mesenchymal gradient through a transcriptional switch involving loss of renal transcription factor TFCP2L1 and gain of a NFE2L2-associated ferroptosis resistance program. SMARCB1 re-expression in cultured RMC cells reactivates TFCP2L1 that relocates SWI/SNF from the promoters of the MYC-driven oncogenic program to the enhancers of TAL identity genes followed by ferroptotic cell death. We further show that RMC is associated with abundant M2-type macrophages and cancer-associated fibroblasts (CAFs) and we identify key regulatory cross-talks that shape this immunosuppressive microenvironment. Together our data describe the molecular events of RMC transformation and identify novel therapeutically targetable vulnerabilities. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/462391v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@152fa6eorg.highwire.dtl.DTLVardef@b76f50org.highwire.dtl.DTLVardef@ed1382org.highwire.dtl.DTLVardef@9be54f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

BRN2 is a non-canonical melanoma tumor-suppressor

While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, we show that BRN2 haplo-insufficiency is sufficient to promote melanoma initiation and metastasis, acting as a non-canonical tumor suppressor. Mechanistically, BRN2 directly modulates PTEN expression, and PI3K signaling, to drive tumor initiation and progression. Collectively our results reveal that somatic deletion of one BRN2 allele elicits melanoma initiation and progression. SIGNIFICANCEHere, we report frequent mono-allelic loss of the transcription factor BRN2 in human cutaneous melanoma metastases. We developed a mouse model for Brn2-deficient melanoma based on the most common alterations (BrafV600E and Pten loss) in human melanoma and established the role of Brn2 as a functional regulator of tumor initiation, tumor growth, and the formation of metastases in vivo. Mechanistically, BRN2 loss increases PI3K-signaling through PTEN repression, either via MITF induction or not. Overall, we describe a novel tumor suppressor of high prevalence in human melanoma that regulates several steps of in vivo melanomagenesis through two previously unknown molecular mechanisms.

cancer biology↗

bioRxiv2020

TFIIH kinase CDK7 antagonizes phenotype switching and emergence of drug tolerance in melanoma

Melanoma cells switch back-and-forth between phenotypes of proliferation and invasion in response to changing microenvironment, driving metastatic progression. We show that inhibition of the TFIIH kinase CDK7 (CDK7i) results in a melanocytic to mesenchymal phenotype switching and acquisition of targeted therapy tolerance. We identify a gene expression program controlled by the transcription factor GATA6, which participates in drug tolerance in mesenchymal-like cells and which is antagonized by CDK7 in melanocytic-like cells. This program emerges concomitantly with loss of melanocyte lineage-specific MITF protein following CDK7i. By dissecting the underlying mechanism, we observe that CDK7 accumulates at the super-enhancer regulating MITF to drive its expression. MITF itself binds to a intronic region of GATA6 to transcriptionally repress it. This molecular cascade antagonizes expression of the GATA6 regulon that only emerges in MITF-low cells of metastatic melanoma. Our work reveals a role for CDK7 in counteracting phenotype switching and activation of a gene expression program mediating multidrug tolerance in melanoma cells.

cell biology↗

bioRxiv2020

Stabilization of β-catenin promotes melanocyte specification at the expense of the Schwann cell lineage

The canonical Wnt/β-catenin pathway governs a multitude of developmental processes in various cell lineages, including the melanocyte lineage. Indeed, β-catenin regulates Mitf-M transcription, the master regulator of this lineage. The first wave of melanocytes to colonize the skin is directly derived from neural crest cells, while a small number of second wave melanocytes is derived from Schwann-cell precursors (SCPs). We investigated the influence of β-catenin in the development of melanocytes of the first and second waves by generating mice expressing a constitutively active form of β-catenin in cells expressing tyrosinase. Constitutive activation of β-catenin did not affect the development of truncal melanoblasts, but led to a marked hyperpigmentation of the paws. By activating β-catenin at various stages of development (E8.5-E11.5), we showed that the activation of β-catenin in bipotent SCPs favored melanoblast specification at the expense of Schwann cells in the limbs within a specific temporal window. In addition, hyperactivation of the Wnt/β-catenin pathway repressed FoxD3 expression, which is necessary for Schwann cell development, through Mitf-M activation. In conclusion, β-catenin overexpression promotes SCP cell-fate decisions towards the melanocyte lineage.Summary statement Activation of β-catenin in bipotent Schwann-cell precursors during a specific developmental window, induces MITF and represses FoxD3 to promote melanoblast cell fate at the expense of Schwann cells in limbs.View Full Text

developmental biology↗

bioRxiv2020

The TFIID subunit Taf4 is required for pancreatic beta cell function and identity.

We selectively inactivated the Taf4 subunit of general transcription factor TFIID in adult murine pancreatic beta cells (BCs). Taf4 inactivation rapidly diminishes expression of critical genes involved in BC function leading to increased glycaemia, lowered plasma insulin levels, defective glucose-stimulated insulin secretion and in the longer term reduced BC mass through apoptosis of a subpopulation of BCs. Nevertheless, glycaemia and blood insulin levels are stabilised after 11 weeks with mutant animals showing long term survival. Bulk RNA-seq and ATAC-seq together with single cell RNA-seq on isolated Langerhans islets show that Taf4 loss leads to a remodelling of chromatin accessibility and gene expression not only in targeted BCs, but also alpha and delta cells. One week after Taf4-loss, cells with mixed BC, alpha and/or delta cell identities were observed as well as a BC population trans-differentiating into alpha-like cells. Computational analysis defines how known critical BC and alpha cell determinants may act in combination with additional transcription factors and the NuRF chromatin remodelling complex to promote BC trans-differentiation.

cell biology↗

bioRxiv2019

CHD4 regulates PADI1 and PADI3 expression linking pyruvate kinase M2 citrullination to glycolysis and proliferation.

CHD3 and CHD4 are mutually exclusive ATPase subunits of the Nucleosome Remodelling and Deacetylation (NuRD) complex that regulates gene expression. CHD4 is essential for growth of multiple patient derived melanoma xenografts and for breast cancer. Here we show that CHD4 regulates expression of PADI1 (Protein Arginine Deiminase 1) and PADI3 in multiple cancer cell types modulating citrullination of three arginines of the allosterically-regulated glycolytic enzyme pyruvate kinase M2 (PKM2). Citrullination reprograms cross-talk between PKM2 ligands lowering its sensitivity to the inhibitors Tryptophan, Alanine and Phenylalanine and promoting activation by Serine. Citrullination thus bypasses normal physiological regulation by low Serine levels to promote excessive glycolysis defining a novel pathway regulating proliferation of melanoma and other cancer cells. We provide unique insight as to how conversion of arginines to citrulline impacts key interactions within PKM2 that act in concert to reprogram its activity as an additional mechanism regulating this important enzyme.

cancer biology↗