Sarah Hazell Pickering

• 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.

• 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.

• 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.

• Potolitsyna, Evdokiia; Pickering, Sarah Jai Hazell; Tooming-Klunderud, Ave; Collas, Philippe & Briand, Nolwenn (2022). De novo annotation of lncRNA HOTAIR transcripts by long-read RNA capture-seq reveals a differentiation-driven isoform switch. BMC Genomics. 23(1). doi: 10.1186/s12864-022-08887-w. Fulltekst i vitenarkiv Vis sammendrag

  Background LncRNAs are tissue-specific and emerge as important regulators of various biological processes and as disease biomarkers. HOTAIR is a well-established pro-oncogenic lncRNA which has been attributed a variety of functions in cancer and native contexts. However, a lack of an exhaustive, cell type-specific annotation questions whether HOTAIR functions are supported by the expression of multiple isoforms. Results Using a capture long-read sequencing approach, we characterize HOTAIR isoforms expressed in human primary adipose stem cells. We find HOTAIR isoforms population displays varied splicing patterns, frequently leading to the exclusion or truncation of canonical LSD1 and PRC2 binding domains. We identify a highly cell type-specific HOTAIR isoform pool regulated by distinct promoter usage, and uncover a shift in the HOTAIR TSS usage that modulates the balance of HOTAIR isoforms at differentiation onset. Conclusion Our results highlight the complexity and cell type-specificity of HOTAIR isoforms and open perspectives on functional implications of these variants and their balance to key cellular processes.

• Potolitsyna, Evdokiia; Pickering, Sarah Jai Hazell; Germier, Thomas Lodewijk Guy; Collas, Philippe & Briand, Nolwenn (2022). Long non-coding RNA HOTAIR regulates cytoskeleton remodeling and lipid storage capacity during adipogenesis. Scientific Reports. 12(1). doi: 10.1038/s41598-022-14296-6. Fulltekst i vitenarkiv Vis sammendrag

  Abstract The long non-coding RNA HOTAIR is the most differentially expressed gene between upper- and lower-body adipose tissue, yet its functional significance in adipogenesis is unclear. We report that HOTAIR expression is transiently induced during early adipogenic differentiation of gluteofemoral adipose progenitors and repressed in mature adipocytes. Upon adipogenic commitment, HOTAIR regulates protein synthesis pathways and cytoskeleton remodeling with a later impact on mature adipocyte lipid storage capacity. Our results support novel and important functions of HOTAIR in the physiological context of adipogenesis.

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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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