Biology subjects

Robin, M.

Publications and source records attributed to Robin, M..

7 recordsLinked to original sources

bioRxiv2026

The Pregnane X Receptor (PXR) contributes to phenotypic plasticity and modulates the sensitivity to targeted therapies in melanoma

The challenge in treating advanced metastatic melanoma lies in the development of therapeutic resistance and the risk of recurrence. Understanding the mechanisms underlying tumor adaptation to treatment is therefore crucial, as they can directly influence therapeutic efficacy. Tolerance to targeted therapies may be influenced by drug transport and metabolism within tumors, processes regulated by numerous genes under the transcriptional control of the nuclear receptor PXR (Pregnane X Receptor, NR1I2). We revealed, for the first time, significant and heterogeneous expression of PXR in human melanoma samples. We previously showed that PXR can be activated by BRAF inhibitors (BRAFi), but not by MEK inhibitors (MEKi), which are currently used in combination for the treatment of BRAF-V600E-mutated melanoma. Here, we investigated whether PXR expression influences melanoma cell sensitivity to MAPK pathway inhibitors. Using BRAF-mutated human melanoma cell lines, we showed that stable PXR expression sensitizes cells to combined BRAFi/MEKi treatment. Transcriptomic analysis further revealed that PXR expression is associated with the upregulation of several phenotypic markers, with MITF identified as a major regulator in untreated PXR-overexpressing cells. These findings suggest that PXR promotes a shift toward a melanocytic phenotype, which is associated with increased sensitivity to BRAFi/MEKi treatment. Characterization of the PXR-associated transcriptional signature in melanoma may therefore have translational value for identifying patients more likely to benefit from targeted therapies and support the development of PXR as a predictive biomarker of therapeutic response.

cancer biology↗

bioRxiv2026

Paleogenomic time series reveal past population dynamics and their relevance for the conservation of the Alpine ibex

Endangered species often suffer from genetic threats such as inbreeding depression, the accumulation of mutation load and the general loss of genetic diversity, which may deprive them from future adaptation. Since the genetic make-up of a species is strongly affected by its evolutionary past, however, interspecific comparisons are difficult and absolute levels of genetic diversity may be a relatively poor predictor of extinction risk. To better interpret current levels of genetic diversity of actively managed species, the comparison of present-day genomic data to that of ancient material pre-dating recent anthropogenic population declines has been advocated, but remains rarely done at the evolutionary time scales necessary to understand past population dynamics. Here we demonstrate the usefulness of deep genomic time series through 40 high quality ancient genomes of the Alpine ibex, which faced near-extinction in the 19th century but has since been reintroduced across the Alps and recovered remarkably. The samples, which span the last 14,000 years, evidence strong and stable population structure at the continental scale, paired with frequent extinction and recolonization events at the local scale. These metapopulation dynamics resulted in small and largely isolated populations, with present-day, reintroduced populations only having 20% to 40% less neutral genetic diversity and 3% higher mutation load, likely due to efficient purging in the past. At the species level, however, the loss of genetic diversity was dramatic and reduced to the small fraction that segregated within the only surviving population in the Gran Paradiso area. Our analyses of ancient metapopulation dynamics in Alpine ibex underscore the importance of a healthy genetic pool for successful recolonization and long-term survival, as well as the real possibility of regional extinctions.

evolutionary biology↗

bioRxiv2025

Evidence of distal regulations orchestrated by RNAs initiating at short tandem repeats

Short Tandem Repeats (STRs), also called microsatellites, correspond to tandemly repeated short DNA motifs (1 to 6 bp) and are one of the most polymorphic and abundant repetitive elements in the human genome. Variations of their length (i.e. number of consecutive repeats) have been implicated in gene expression regulation (termed expression(e)STRs). Using captrapping followed by long read sequencing, we discovered that STRs can host transcription start sites, the presence of which depends mainly on STR flanking sequences. Here, we investigate the effect of SNPs located in these sequences and ask whether STR-initiating RNAs have regulatory potential. First, we develop fully interpretable deep learning-based models, called Modular Neural Networks, able to predict, for each STR class, the level of RNAs using 101bp-long sequences encompassing STRs. Analysis of MNN filters allows us to identify multiple regulatory elements and candidate transcription factors. Second, leveraging genome sequencing and gene expression data from the Genotype-Tissue Expression project, we use the output of our models to link the levels of STR-initiating RNAs to the expression of nearby genes. We identify 14,340 significant associations (coined RNA(r)STRs) and illustrate how this novel resource can help interpret non-coding variants associated with complex traits and diseases. Third, we unveil an intricate transcriptional interplay between STR-initiating RNAs and Alu repeats that may couple their regulatory actions, extending both the nature and the functional importance of non-coding transcription and shedding new light on the complexity of distal regulations orchestrated by repeated sequences.

genomics↗

bioRxiv2023

Facilitated introgression from domestic goat into Alpine ibex at immune loci

Introgression is expected to be adaptive at loci under balancing selection, for instance at loci relevant for the immune response, but these loci generally also contain ancient polymorphisms. Ancient genomics is a promising tool to detect recent introgression and disentangle it from ancient polymorphisms. Alpine ibex (Capra ibex), a wild goat species native to the European Alps, faced near-extinction two centuries ago, but has recovered thanks to successful restoration programs. Previously, signals of introgression from the domestic goat (Capra aegagrus hircus) into the Alpine ibex genome were found at the major histocompatibility complex. This introgression was suggested to potentially be adaptive since it introduced new diversity at a gene locus important for immunity. But no genome-wide analyses of introgression have been performed to confirm the potential relevance of immune loci. Here we take advantage of two ancient whole genomes of Alpine ibex combined with 29 modern Alpine ibex genomes and 31 genomes representing six related Capra species to investigate genome-wide patterns of introgression. Our complementary analysis of putatively introgressed haplotypes and demographic modelling suggests 2.3% recent domestic goat ancestry among wild Alpine ibex. The introgression was estimated to have happened during the last 300 years coinciding with the time when the species had very small population size. Further analysis suggested an enrichment of immune-related genes, where the adaptive value of alternative alleles may give individuals with otherwise depleted genetic diversity a selective advantage.

evolutionary biology↗

bioRxiv2023

The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in HCT116 colon cancer cells

YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the P73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using several colorectal cancer cell lines, we show here that oxaliplatin treatment led to a dramatic core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of P73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed an antagonistic with oxaliplatin in co-treatments. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and P53 activity pushes cells towards apoptosis.

cancer biology↗

bioRxiv2021

Ancient mitogenomes unravel massive genetic diversity loss during near extinction of Alpine ibex

Population bottlenecks can have dramatic consequences for the health and long-term survival of a species. A recent bottleneck event can also largely obscure our understanding of standing variation prior to the contraction. Historic population sizes can be modeled based on extant genomics, however uncertainty increases with the severity of the bottleneck. Integrating ancient genomes provides a powerful complement to retrace the evolution of genetic diversity through population fluctuations. Here, we recover 15 high-quality mitogenomes of the once nearly extinct Alpine ibex spanning 8601 {+/-} 33 BP to 1919 CE and combine these with 60 published modern genomes. Coalescent demography simulations based on modern genomes indicate population fluctuations matching major climatic change over the past millennia. Using ancient genomes, we show that mitochondrial haplotype diversity has been reduced to a fifth of the pre-bottleneck diversity with several highly differentiated mitochondrial lineages having co-existed historically. The main collapse of mitochondrial diversity coincided with human settlement expansions in the Middle Ages. The near extinction severely reduced the mitochondrial diversity. After recovery, one lineage was spread and nearly fixed across the Alps due to recolonization efforts. Contrary to expectations, we show that a second ancestral mitochondrial lineage has survived in an isolated population further south. Our study highlights that a combined approach integrating genomic data of ancient, historic and extant populations unravels major long-term population fluctuations.

evolutionary biology↗

bioRxiv2019

European common frog (Rana temporaria) recolonised Switzerland from multiple glacial refugia in northern Italy via trans- and circum-Alpine routes

The high mountain ranges of western Europe have had a profound effect on the recolonisation of Europe from glacial refugia. The Alps present a particularly interesting case, because they present an absolute barrier to dispersal to most lineages, obstructing recolonisation from multiple refugia in the Italian Alps. Here we investigate the effect of the European Alps on the the phylogeographic history of Rana temporaria across its range in Switzerland. Based on partial cytochrome b and COX1 sequences we find two mitochondrial lineages that occur roughly north and south of the alpine ridge bisecting Switzerland, with contact zones between them in the east and west. The northern haplogroup falls within the previously identified common western European haplogroup, while the southern haplogroup is unique to Switzerland. We find that the lineages diverged ~110 kya, approximately the onset of the last glacial maximum, indicative of origins in separate refugia. Phylogenetic analyses suggest that the lineages originate from two refugia in northern Italy, and colonised Switzerland via trans- and curcum-alpine routes. Our results show that the European Alps is a semi-permeable barrier to dispersal for R. temporaria, and have contributed to the complex recolonisation history of Switzerland.

evolutionary biology↗