Philippe Collas

• Pickering, Sarah Jai Hazell; Galigniana, Natalia Maricel; Abdelhalim, Mohamed; Sørensen, Anita Løvstad; Madsen-Østerbye, Julia-Kristina & Zucknick, Manuela [Vis alle 8 forfattere av denne artikkelen] (2026). Multimodal epigenetic and enhancer network remodeling shape the transcriptional landscape of human beige adipocytes. Communications Biology. doi: 10.1038/s42003-025-09469-8. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Epigenetic regulation is a key determinant of adipocyte fate, driving the differentiation toward white or thermogenic beige phenotypes in response to environmental cues. To dissect the mechanisms orchestrating this plasticity in human adipocytes, we conducted an integrative analysis of transcriptomic, epigenomic and enhancer connectome dynamics throughout white and beige adipogenesis. Using a machine learning approach, we show that the white transcriptional program is tightly linked to promoter-level modulation of H3K27ac and chromatin accessibility, whereas the beige-specific induction of mitochondrial genes is driven by promoter remodeling of H3K4me3, underscoring distinct epigenetic mechanisms for white or beige specification. Adipocyte beiging is accompanied by a targeted reorganization of the 3D genome, characterized by increased recruitment of short-range enhancers controlling thermogenesis genes, enriched for C/EBP transcription factor binding sites. Our findings highlight the multimodal regulation of the beige adipocyte fate, driven by the interplay of chromatin state transitions, enhancer rewiring, and transcription factor dynamics.

• Dufour, Damien; Bryne, Sandra Kristine Stølen; Dapsance, Florian; Ferrito, Noemi; Plotton, Ingrid & Dalen, Knut Tomas [Vis alle 9 forfattere av denne artikkelen] (2025). Mechanisms of sexually dimorphic adipose tissue remodelling upon prolonged breastfeeding. bioRxiv (preprint article). doi: 10.1101/2025.09.05.674416. Fulltekst i vitenarkiv Vis sammendrag

  Early developmental cues exert lasting influence on the adipose tissue function and the metabolic health throughout adulthood. In mice, adipose tissue remodelling during the weaning transition programs long-term tissue plasticity, setting its capacity for expansion and thermogenesis in response to environmental stimuli. However, the mechanisms driving this remodelling, and the role of weaning-associated dietary changes in this process, are unknown. Here, we characterise the emergence of sexually dimorphic patterns of adipose tissue distribution and function during the post-weaning period. As subcutaneous adipocytes acquire a white phenotype, the tissue microenvironment undergoes a coordinated remodelling, including reduced innervation and an increase in immune cell content. Using a model of prolonged breastfeeding, we show that it promotes adipose tissue expansion through sex-dependent mechanisms, stimulating progenitor proliferation in males and adipocyte hypertrophy in females. In males, this is accompanied by accelerated tissue whitening, which we link to enhanced clearance of extracellular noradrenaline by mature adipocytes. Our findings reveal sex- and diet-dependent mechanisms governing adipose tissue maturation and highlight how early life nutritional cues shape the microenvironment and function of mature adipocytes. Highlights - The peri-weaning period associates with sexually dimorphic remodelling of the adipose tissue - Whitening of the adipose tissue associates with immune infiltration and decrease innervation in both sexes - Prolonged breastfeeding prevents drop in proliferation in males - Whitening is accelerated in males during prolonged breastfeeding

• Rossini, Roberto; Oshaghi, Mohammadsaleh; Nekrasov, Maxim; Bellanger, Aurélie Nathalie Pascale; Domaschenz, Renae & Dijkwel, Yasmin [Vis alle 13 forfattere av denne artikkelen] (2025). Loss of multilevel 3D genome organization during breast cancer progression. Genome Research. ISSN 1088-9051. s. 1–18. doi: 10.1101/gr.280791.125. Fulltekst i vitenarkiv Vis sammendrag

  Breast cancer entails intricate alterations in genome organization and expression. However, how three-dimensional (3D) chromatin structure changes in the progression from a normal to a breast cancer malignant state remains unknown. To address this, we have conducted an analysis combining Hi-C data with lamina-associated domains (LADs), epigenomic marks, and gene expression in an in vitro model of breast cancer progression. Our results reveal that although the fundamental properties of topologically associating domains (TADs) are overall maintained, significant changes occur in the organization of compartments and subcompartments. These changes are closely correlated with alterations in the expression of oncogenic genes. We also observe a restructuring of TAD–TAD interactions, coinciding with a loss of spatial compartmentalization and radial positioning of the 3D genome. Notably, we identify a previously unrecognized interchromosomal insertion event, wherein a locus on Chromosome 8 housing the MYC oncogene is inserted into a highly active subcompartment on Chromosome 10. This insertion is accompanied by the formation of de novo enhancer contacts and activation of MYC , illustrating how structural genomic variants can alter the 3D genome during oncogenesis. In summary, our findings provide evidence for the loss of genome organization at multiple scales during breast cancer progression, revealing novel relationships between genome 3D structure and oncogenic processes.

• Vatier, Camille; Araújo-Vilar, David; Akinci, Baris; Arnould, Thierry; Beaupère, Carine & Bismuth, Elise [Vis alle 29 forfattere av denne artikkelen] (2025). Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip) Paris, France, 20–21 May 2025. Annales d'Endocrinologie. ISSN 0003-4266. 86(5), s. 1–12. doi: 10.1016/j.ando.2025.102432. Fulltekst i vitenarkiv Vis sammendrag

  Lipodystrophy syndromes are rare diseases characterized by anatomical and functional defects of adipose tissue, frequently leading to severe insulin resistance-associated metabolic complications. Subtypes of lipodystrophy syndromes differ in: their clinical presentation, with generalized or partial loss of adipose tissue; in their origin, either genetic or acquired; and in their comorbidities, forming a heterogeneous group of disorders of different severity. The European Consortium of Lipodystrophies (ECLip) was founded in 2014 as a non-profit network of health professionals, scientists and patient associations. ECLip aims to promote international collaborations to increase pathophysiological and clinical knowledge, and improve the management of lipodystrophy syndromes. ECLip now comprises 59 groups from 30 countries from Europe and beyond. The consortium developed in parallel to the increased awareness of clinical diagnosis, the growing scientific interest for these diseases at the crossroads between adipose tissue biology, whole body metabolism, genetics and immunity, and to the emergence of new pharmacological approaches. The ECLip congress, held every 18 months, aims to discuss the recent achievements and projects in the field of lipodystrophies, to consolidate ECLip activities and to promote future collaborations, highlighting clinical and fundamental aspects as well as patients’ perspectives. Oral communications presented during the meeting in Paris, France, in 2025 are summarized in these minutes.

• Galigniana, Natalia Maricel; Abdelhalim, Mohamed Ibrahim Mohamed; Collas, Philippe & Sæther, Thomas (2024). Transcriptional and Metabolic Changes Following Repeated Fasting and Refeeding of Adipose Stem Cells Highlight Adipose Tissue Resilience. Nutrients. 16(24). doi: 10.3390/nu16244310. Fulltekst i vitenarkiv Vis sammendrag

  Background: Obesity and related metabolic disorders have reached epidemic levels, calling for diverse therapeutic strategies. Altering nutrient intake, timing and quantity by intermittent fasting seems to elicit beneficial health effects by modulating endocrine and cell signaling networks. This study explores the impact of cyclic nutrient availability in the form of every-other-day fasting (EODF) on human adipose stem cells (ASCs). Methods: We subjected ASCs to repeated fasting/refeeding (F/R) cycles, mimicking low glucose/high fatty acid (LGHF) conditions, and assessed phenotypic and transcriptomic changes, lipid storage capacity, insulin sensitivity, and differentiation potential. Results: Four consecutive F/R cycles induced significant changes in adipogenic gene expression, with upregulation of FABP4 and PLIN1 during fasting, and increased lipid storage in the ASCs. Upon differentiation, ASCs exposed to LGHF conditions retained a transient increase in lipid droplet size and altered fatty acid metabolism gene expression until day 9. However, these changes dissipated by day 15 of differentiation, suggesting a limited duration of fasting-induced transcriptional and adipogenic memory. Despite initial effects, ASCs showed resilience, returning to a physiological trajectory during differentiation, with respect to gene expression and lipid metabolism. Conclusions: These findings suggest that the long-term effects of EODF on the ASC niche may be transient, emphasizing the ability of the adipose tissue to adapt and restore homeostasis.

• Pickering, Sarah Jai Hazell; Abdelhalim, Mohamed Ibrahim Mohamed; Collas, Philippe & Briand, Nolwenn (2024). Alternative isoform expression of key thermogenic genes in human beige adipocytes. Frontiers in Endocrinology. 15. doi: 10.3389/fendo.2024.1395750. Fulltekst i vitenarkiv Vis sammendrag

  Background: The beneficial effect of thermogenic adipocytes in maintaining body weight and protecting against metabolic disorders has raised interest in understanding the regulatory mechanisms defining white and beige adipocyte identity. Although alternative splicing has been shown to propagate adipose browning signals in mice, this has yet to be thoroughly investigated in human adipocytes. Methods: We performed parallel white and beige adipogenic differentiation using primary adipose stem cells from 6 unrelated healthy subjects and assessed differential gene and isoform expression in mature adipocytes by RNA sequencing. Results: We find 777 exon junctions with robust differential usage between white and beige adipocytes in all 6 subjects, mapping to 562 genes. Importantly, only 10% of these differentially spliced genes are also differentially expressed, indicating that alternative splicing constitutes an additional layer of gene expression regulation during beige adipocyte differentiation. Functional classification of alternative isoforms points to a gain of function for key thermogenic transcription factors such as PPARG and CITED1, and enzymes such as PEMT, or LPIN1. We find that a large majority of the splice variants arise from differential TSS usage, with beige-specific TSSs being enriched for PPARγ and MED1 binding compared to white-specific TSSs. Finally, we validate beige specific isoform expression at the protein level for two thermogenic regulators, PPARγ and PEMT. Discussion: These results suggest that differential isoform expression through alternative TSS usage is an important regulatory mechanism for human adipocyte thermogenic specification.

• Potolitsyna, Evdokiia; Pickering, Sarah Jai Hazell; Bellanger, Aurelie Nathalie Pascale; Germier, Thomas Lodewijk Guy; Collas, Philippe & Briand, Nolwenn (2024). Cytoskeletal rearrangement precedes nucleolar remodeling during adipogenesis. Communications Biology. 7. doi: 10.1038/s42003-024-06153-1. Fulltekst i vitenarkiv Vis sammendrag

  Differentiation of adipose progenitor cells into mature adipocytes entails a dramatic reorganization of the cellular architecture to accommodate lipid storage into cytoplasmic lipid droplets. Lipid droplets occupy most of the adipocyte volume, compressing the nucleus beneath the plasma membrane. How this cellular remodeling affects sub-nuclear structure, including size and number of nucleoli, remains unclear. We describe the morphological remodeling of the nucleus and the nucleolus during in vitro adipogenic differentiation of primary human adipose stem cells. We find that cell cycle arrest elicits a remodeling of nucleolar structure which correlates with a decrease in protein synthesis. Strikingly, triggering cytoskeletal rearrangements mimics the nucleolar remodeling observed during adipogenesis. Our results point to nucleolar remodeling as an active, mechano-regulated mechanism during adipogenic differentiation and demonstrate a key role of the actin cytoskeleton in defining nuclear and nucleolar architecture in differentiating human adipose stem cells.

• Benarroch, Louise; Madsen-Østerbye, Julia-Kristina; Abdelhalim, Mohamed Ibrahim Mohamed; Mamchaoui, Kamel; Ohana, Jessica & Bigot, Anne [Vis alle 10 forfattere av denne artikkelen] (2023). Cellular and Genomic Features of Muscle Differentiation from Isogenic Fibroblasts and Myoblasts. Cells. 12(15). doi: 10.3390/cells12151995. Fulltekst i vitenarkiv Vis sammendrag

  The ability to recapitulate muscle differentiation in vitro enables the exploration of mechanisms underlying myogenesis and muscle diseases. However, obtaining myoblasts from patients with neuromuscular diseases or from healthy subjects poses ethical and procedural challenges that limit such investigations. An alternative consists in converting skin fibroblasts into myogenic cells by forcing the expression of the myogenic regulator MYOD. Here, we directly compared cellular phenotype, transcriptome, and nuclear lamina-associated domains (LADs) in myo-converted human fibroblasts and myotubes differentiated from myoblasts. We used isogenic cells from a 16-year-old donor, ruling out, for the first time to our knowledge, genetic factors as a source of variations between the two myogenic models. We show that myo-conversion of fibroblasts upregulates genes controlling myogenic pathways leading to multinucleated cells expressing muscle cell markers. However, myotubes are more advanced in myogenesis than myo-converted fibroblasts at the phenotypic and transcriptomic levels. While most LADs are shared between the two cell types, each also displays unique domains of lamin A/C interactions. Furthermore, myotube-specific LADs are more gene-rich and less heterochromatic than shared LADs or LADs unique to myo-converted fibroblasts, and they uniquely sequester developmental genes. Thus, myo-converted fibroblasts and myotubes retain cell type-specific features of radial and functional genome organization. Our results favor a view of myo-converted fibroblasts as a practical model to investigate the phenotypic and genomic properties of muscle cell differentiation in normal and pathological contexts, but also highlight current limitations in using fibroblasts as a source of myogenic cells.

• Madsen-Østerbye, Julia-Kristina; Abdelhalim, Mohamed Ibrahim Mohamed; Pickering, Sarah Jai Hazell & Collas, Philippe (2023). Gene Regulatory Interactions at Lamina-Associated Domains. Genes. 14(2), s. 1–15. doi: 10.3390/genes14020334. Fulltekst i vitenarkiv Vis sammendrag

  The nuclear lamina provides a repressive chromatin environment at the nuclear periphery. However, whereas most genes in lamina-associated domains (LADs) are inactive, over ten percent reside in local euchromatic contexts and are expressed. How these genes are regulated and whether they are able to interact with regulatory elements remain unclear. Here, we integrate publicly available enhancer-capture Hi-C data with our own chromatin state and transcriptomic datasets to show that inferred enhancers of active genes in LADs are able to form connections with other enhancers within LADs and outside LADs. Fluorescence in situ hybridization analyses show proximity changes between differentially expressed genes in LADs and distant enhancers upon the induction of adipogenic differentiation. We also provide evidence of involvement of lamin A/C, but not lamin B1, in repressing genes at the border of an in-LAD active region within a topological domain. Our data favor a model where the spatial topology of chromatin at the nuclear lamina is compatible with gene expression in this dynamic nuclear compartment.

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• Pickering, Sarah Jai Hazell; Briand, Nolwenn; Collas, Philippe & Zucknick, Manuela (2025). White and beige adipogenesis: Transcriptomic and epigenetic insights into human adipocyte plasticity. Universitetet i Oslo. ISSN 9788234806742. Fulltekst i vitenarkiv Vis sammendrag

  Adipose tissue plasticity plays a critical role in maintaining metabolic homeostasis and represents an important focus of research in a world with a growing prevalence of obesity and type 2 diabetes. The presence of thermogenic beige adipocytes within white adipose tissue correlates with a lean, metabolically healthy phenotype in adults. Yet, the mechanisms underlying individual variations in thermogenic capacity remain poorly understood. To understand the regulation of beige adipocyte identity and lineage specification, we investigated the transcriptome and 3D epigenome of human white and beige mature adipocytes and mapped early adipogenic differentiation at single-cell resolution. As a model, we differentiated primary adipose stem cells isolated from six unrelated individuals in the presence or absence of the beiging agent rosiglitazone, generating matched beige and white adipocytes. We define a range of cell states among adipose progenitors during early white and beige adipogenesis, including several bipotential progenitor populations that can produce both white and beige adipocytes. Further, we characterised the transcriptomic and epigenetic landscape of mature adipocytes and found that alternative isoform usage makes a significant contribution to the functional transcriptome of beige versus white adipocytes. We discovered a novel beige-specific isoform of PEMT and alternative TSS usage of key transcription factor PPARy. In addition, we identified increased active epigenetic marks and enhancer contacts in beige adipocytes. White adipocytes, in comparison, have an enrichment for different epigenetic markers, highlighting distinctive features of the epigenome between beige and white adipocytes. Together this thesis provides insights into the transcriptional heterogeneity of adipose progenitors, early adipogenesis and the epigenetic regulation of healthy white and beige cultured adipocytes.

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