Biology subjects

Le Duc, D.

Publications and source records attributed to Le Duc, D..

6 recordsLinked to original sources

bioRxiv2026

A conserved transcriptomic model defines metabolic resilience and vulnerability in obesity

BackgroundObesity arises from a complex interplay of genetic and environmental factors, with alterations of transcriptional networks that integrate metabolic, immune, and regulatory pathways. Conventional measures such as body mass index (BMI) quantify body size but fail to capture the molecular heterogeneity underlying divergent metabolic outcomes. We therefore sought to construct a gene expression-based transcriptomic representation of obesity, using BMI as a practical training anchor, and to use this framework to delineate transcriptional programs associated with metabolically healthy and pathogenic obesity, with subsequent projection to mouse transcriptomic data for cross-species validation. MethodsTranscriptome data of human visceral adipose tissue (N= 1,298) were used to derive the transcriptomic BMI model, and genes contributing to the model were functionally annotated by gene set enrichment analysis. The human-trained model was subsequently applied to mouse selection lines (N = 18) with divergent obesity phenotypes. In the human cohort, post hoc stratification into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) groups was performed using a downstream classification framework incorporating observed BMI together with predicted BMI, to assess whether model-derived predicted BMI reflected obesity-related pathophysiologic status. ResultsModel-selected genes were involved in coordinated regulation of lipid metabolism, immune activation, and growth signaling, extending to mitochondrial and translational pathways. Cross-species analyses uncovered conserved metabolic polarization: DU6 mice exhibited lipid-anabolic and inflammatory remodeling, whereas DU6P mice displayed oxidative, mitochondrial, and GH-axis-enriched transcriptional states. In human cohorts, MHO individuals showed upregulation of mitochondrial energetics and protein synthesis, while MUO individuals were characterized by increased autophagy, lipid catabolism, and stress-adaptive signaling on the transcriptional level. Together, these findings define a conserved molecular continuum linking oxidative efficiency to metabolic health and inflammation to metabolic vulnerability. ConclusionsThis integrative transcriptomic framework bridges human and mouse adipose biology to uncover conserved mechanisms underlying obesity phenotypes. By contrasting mitochondrial and translational programs with inflammatory and catabolic pathways, it provides mechanistic insight into metabolic resilience and a foundation for precision approaches to obesity management.

systems biology↗

bioRxiv2023

Drosophila Bchs overexpression recapitulates human WDFY3 neurodevelopmental phenotypes with implications for glial cell involvement in altered head circumference

The autophagy adaptor WDFY3 is linked to neurodevelopmental delay and altered brain size. Loss-of-function variants are associated with an increased brain size in both humans and mice. We thus, hypothesized that the microcephaly observed in some of the patients may be related to a gain-of-function of the WDFY3 gene product. While the role of WDFY3 loss-of-function has been studied extensively in neurons, little is known about the effects of WDFY3 overexpression in different neural cell types. We utilized a Drosophila melanogaster overexpression model to investigate the effect of the WDFY3 ortholog Bchs (blue cheese) on development, CNS size, and gene expression profiles. Glial and neuronal overexpression of Bchs impaired CNS development, locomotion and autophagy. Glial overexpression of Bchs also altered CNS size significantly. We identified 79 genes that were differentially expressed and overlapped in flies that overexpress Bchs in glial and neuronal cells, respectively. Additionally, upon neuronal Bchs overexpression differentially expressed genes clustered in gene ontology categories associated with autophagy and mitochondria. Our data indicate that WDFY3/Bchs overexpression in both neurons and glial cells results in impaired neural development, which corresponds to symptoms observed in WDFY3-related neurodevelopmental delay.

neuroscience↗

bioRxiv2022

Interactive webtool for analyzing drug sensitivity and resistance associated with genetic signatures of cancer cell lines

A wide therapeutic repertoire has become available to oncologists including radio- and chemotherapy, small molecules and monoclonal antibodies. However, drug efficacy can be limited by genetic changes that allow cancer cells to escape therapy. Here, we designed a webtool that facilitates the data analysis of the Genomics of Drug Sensitivity in Cancer (GDSC) database on 265 approved compounds in association with a plethora of genetic changes documented for 1001 cell lines in the Cancer Cell Line Encyclopedia (CCLE, cBioPortal). The webtool computes odds ratios of drug resistance for a queried set of genetic alterations. It provides results on the efficacy of single or groups of compounds assigned to cellular signaling pathways. Using this webtool we replicated known genetic drivers and identified new candidate genes, germline variants, co-mutation, and pharmacogenomic modifiers of both cancer drug resistance and drug repurposing. Webtool availability: https://tools.hornlab.org/GDSC/. Author SummaryTumors develop through uncontrolled cell growth enabled by various alterations that create tumor heterogeneity. Changes of the genome and thus cancer cells cause every patient to react differently to drugs and can lead to drug resistance in cancer therapies. To overcome drug resistance, researchers focus on developing personalized therapies. Here, we provide a straightforward tool to test public in vitro drug sensitivity data on a range of drugs for custom analyses of genetic changes. This may inform the identification of potential drug candidates and improve our understanding of signaling pathways as we can test drug response with custom sets of genetic changes according to specific research questions. The tool and underlying code can be adapted to larger drug response datasets and other data types, e.g. metabolic data, to help structure and accommodate the increasingly large biomedical knowledge base.

cancer biology↗

bioRxiv2021

PTEN regulates adipocyte progenitor growth, differentiation and cellular aging

The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN Hamartoma Tumor Syndrome (PHTS), associated with lipoma development in children. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. Adipocyte progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, while APCs from PHTS patients lipomas retain their adipogenic potential over a prolonged period. To investigate the role of PTEN in adipose tissue development we performed functional assays and RNA sequencing of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR lead to an enhanced proliferation and differentiation of APCs. FOXO1 was downregulated on the mRNA level while inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis activating transcription factor SREBP1. SREBP1 levels were higher after PTEN knockdown and may account for the enhanced adipogenesis. To validate this we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by a SREBP1 downregulation. We observed that PTEN levels were upregulated during long term culture of wild type APCs. PTEN CRISPR cells showed less senescence compared to controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA sequencing of PTEN knockdown vs. control cells. These results provide evidence that PTEN is involved in the regulation of APCs proliferation, differentiation and senescence, thereby contributing to aberrant adipose tissue growth in PHTS patients.

cell biology↗

bioRxiv2020

Ecological specialisation and evolutionary reticulation in extant Hyaenidae

During the Miocene, Hyaenidae was a highly diverse family of Carnivora that has since been severely reduced to four extant genera, each of which contains only a single species. These species include the bone-cracking spotted, striped, and brown hyenas, and the specialised insectivorous aardwolf. Previous genome studies have analysed the evolutionary histories of the spotted and brown hyenas, but little is known about the remaining two species. Moreover, the genomic underpinnings of scavenging and insectivory, defining traits of the extant species, remain elusive. To tackle these questions, we generated an aardwolf genome and analysed it together with those from the other three species. We provide new insights into the evolutionary relationships between the species, the genomic underpinnings of their scavenging and insectivorous lifestyles, and their respective genetic diversities and demographic histories. High levels of phylogenetic discordance within the family suggest gene flow between the aardwolf lineage and the ancestral brown/striped hyena lineage. Genes related to immunity and digestion in the bone-cracking hyenas and craniofacial development in the aardwolf showed the strongest signals of selection in their respective lineages, suggesting putative key adaptations to carrion or termite feeding. We also found a family-wide expansion in olfactory receptor genes suggesting that an acute sense of smell was a key early adaptation for the Hyaenidae family. Finally, we report very low levels of genetic diversity within the brown and striped hyenas despite no signs of inbreeding, which we putatively link to their similarly slow decline in Neover the last [~]2 million years. We found much higher levels of genetic diversity in both the spotted hyena and aardwolf and more stable population sizes through time. Taken together, these findings highlight how ecological specialisation can impact the evolutionary history, demographics, and adaptive genetic changes of a lineage.

evolutionary biology↗

bioRxiv2019

Scientific evaluation of negative exome sequencing followed by systematic scoring of candidate genes to decipher the genetics of neurodevelopmental disorders

BackgroundDeciphering the monogenetic causes of neurodevelopmental disorders (NDD) is an important milestone to offer personalized care. But the plausibility of reported candidate genes in exome studies often remains unclear, which slows down progress in the field.\n\nMethodsWe performed exome sequencing (ES) in 198 cases of NDD. Cases that remained unresolved (n=135) were re-investigated in a research setting. We established a candidate scoring system (CaSc) based on 12 different parameters reflecting variant and gene attributes as well as current literature to rank and prioritize candidate genes.\n\nResultsIn this cohort, we identified 158 candidate variants in 148 genes with CaSc ranging from 2 to 11.7. Only considering the top 15% of candidates, 14 genes were already published or funneled into promising validation studies.\n\nConclusionsWe promote that in an approach of case by case re-evaluation of primarily negative ES, systematic and standardized scoring of candidate genes can and should be applied. This simple framework enables better comparison, prioritization, and communication of candidate genes within the scientific community. This would represent an enormous benefit if applied to the tens of thousands of negative ES performed in routine diagnostics worldwide and speed up deciphering the monogenetic causes of NDD.

genetics↗