Biology subjects

Collas, P.

Publications and source records attributed to Collas, P..

10 recordsLinked to original sources

bioRxiv2025

Mechanisms of sexually dimorphic adipose tissue remodelling upon prolonged breastfeeding

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

physiology↗

bioRxiv2025

Multimodal epigenetic and enhancer network remodeling shape the transcriptional landscape of beige adipocytes

Epigenetic regulation is a key determinant of adipocyte fate and function, conferring phenotypic plasticity to adipose tissue in response to metabolic and thermal challenges. To understand the spatiotemporal regulation of chromatin during the establishment of a beige thermogenic adipocyte phenotype, we analyzed the transcriptomic, epigenetic, and enhancer connectome dynamics during white and beige adipogenesis. Using a machine learning approach, we find that the white-specific transcriptional program is associated with promoter modulations of H3K2ac levels and chromatin accessibility. In contrast, beige-specific mitochondrial gene expression correlates with promoter changes in H3K4me3 levels. Adipocyte beiging is also mediated by a remodeling of the 3D genome involving the recruitment of short range enhancers targeting fatty acid oxidation and thermogenic genes. These increased promoter-enhancer contacts correlate with increased chromatin opening at sites enriched for C/EBP transcription factor motifs. We notably identify the C/EBP transcription factor NFIL3 as differentially bound between white and beige adipocytes at enhancers regulating PDK4, a key metabolic switch promoting fatty acid oxidation. Our results highlight a multimodal, pathway-specific regulation of the transcriptional program underlying the beige adipocyte phenotype.

genomics↗

bioRxiv2023

Multi-level 3D genome organization deteriorates during breast cancer progression

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 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 while 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 to drive oncogenic states. 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.

genomics↗

bioRxiv2023

Active maintenance of CD8+ T cell naivety through regulation of global genome architecture

The differentiation of naive CD8+ cytotoxic T lymphocytes (CTLs) into effector and memory states results in large scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organisation reflect or underpin these transcriptional programs. We utilised Hi-C to map changes in the spatial organisation of long-range genome contacts within naive, effector and memory virus-specific CD8+ T cells. We observed that the architecture of the naive CD8+ T cell genome was distinct from effector and memory genome configurations with extensive changes within discrete functional chromatin domains. However, deletion of the BACH2 or SATB1 transcription factors was sufficient to remodel the naive chromatin architecture and engage transcriptional programs characteristic of differentiated cells. This suggests that the chromatin architecture within naive CD8+ T cells is preconfigured to undergo autonomous remodelling upon activation, with key transcription factors restraining differentiation by actively enforcing the unique naive chromatin state. One Sentence SummaryCD8+ T cell naivety is actively maintained by transcription factors that enforce a distinct, naive chromatin architecture. HighlightsO_LICD8+ T cell differentiation states are underscored by distinct chromatin looping architectures. C_LIO_LIChromatin loops juxtapose CTL state appropriate enhancers, transcription factors and genes. C_LIO_LIEffector and memory CTLs have similar genome architectures, explaining rapid memory recall. C_LIO_LICTL differentiation is restrained by BACH2 and SATB1, which enforce a naive loop architecture. C_LI

immunology↗

bioRxiv2022

Eight principal chromatin states functionally segregate the fly genome into developmental and housekeeping roles

Different chromatin forms, or states, represent a fundamental means of controlling gene regulation. Chromatin states have been studied through either the distribution of histone modifications (e.g. 1-5) or more rarely via the occupancy of chromatin proteins 6-8. However, these two approaches disagree on the nature and composition of active chromatin states 2,9 and modelling chromatin via both histone marks and chromatin proteins has been lacking. Here, combining protein and histone mark profiles, we show that chromatin in Drosophila melanogaster is organised into eight principle chromatin states that have consistent forms and constituents across cell types. These states form through the association of the Swi/Snf chromatin remodelling complex, Polycomb Group (PcG)/H3K27me3, HP1a/H3K9me3 or H3K36me3 complexes with either active complexes (RNA Pol/COM-PASS/H3K4me3/NuRF) or repressive marks (histone H1 and nuclear lamin occupancy). Enhancers, core promoters, transcription factor motifs, and gene bodies show distinct chromatin state preferences that separate by developmental and housekeeping/metabolic gene ontology. Within the 3D genome, chromatin states add an additional level of compartmentalisation through self-association of topologically associated domains (TADs) of the same state. Our results suggest that the epigenetic landscape is organised by the binding of chromatin remodellers and repressive complexes, and that through chromatin states the genome is fundamentally segregated into developmental and housekeeping/metabolic roles.

genomics↗

bioRxiv2022

De novo annotation of lncRNA HOTAIR transcripts by long-read RNA capture-seq reveals a differentiation-driven isoform switch

BackgroundLncRNAs 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. ResultsUsing a capture long-read sequencing approach, we characterize HOTAIR isoforms expressed in human primary adipose stem cells. We identify a highly cell type-specific HOTAIR isoform and uncover a shift in the HOTAIR isoform balance at differentiation onset. Composition of the HOTAIR isoform pool is regulated by distinct promoter usage and is under control of hormonal and nutrient-sensing pathways. ConclusionOur 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.

genomics↗

bioRxiv2020

TAD cliques predict key features of chromatin organization

Processes underlying genome 3D organization and domain formation in the mammalian nucleus are not completely understood. Multiple processes such as transcriptional compartmentalization, DNA loop extrusion and interactions with the nuclear lamina dynamically act on chromatin at multiple levels. Here, we explore long-range interaction patterns between topologically associated domains (TADs) in several cell types. We find that this is connected to many key features of chromatin organization, including open and closed compartments, compaction and loop extrusion processes. We find that domains that form large TAD cliques tend to be repressive across cell types, when comparing gene expression, LINE/SINE repeat content and chromatin subcompartments. Further, TADs in large cliques are larger in genomic size, less dense and depleted of convergent CTCF motifs, in contrast to smaller and denser TADs formed by a loop extrusion processes. Our results shed light on the organizational principles that govern repressive and active domains in the human genome.

genomics↗

bioRxiv2019

Rhythmic chromatin interactions with lamin B1 reflect stochasticity in variable lamina-associated domains during the circadian cycle

Many mammalian genes exhibit circadian expression patterns concordant with periodic binding of transcription factors, chromatin modifications and chromosomal interactions. Here, we report periodic interactions of chromatin with nuclear lamins, suggesting rhythmic associations with the nuclear lamina. Entrainment of the circadian clock is accompanied in mouse liver by a gain of lamin B1-chromatin interactions, followed by oscillations in these interactions at hundreds of lamina-associated domains (LADs). A subset of these oscillations exhibit distinct 12, 18, 24 or 30-h periodicity in our dataset, and affect one or both LAD borders or entire stand-alone LADs. However, most LADs are conserved during the circadian cycle, and periodic LADs are seldom occurrences rather than dominant features of variable LADs. Periodic LADs display oscillation asynchrony between 5 and 3 LAD borders, and are uncoupled from periodic gene expression within or in vicinity of these LADs. Accordingly, periodic genes, including central clock-control genes, are often located megabases away from LADs, suggesting residence in a transcriptionally permissive environment throughout the circadian cycle. Autonomous oscillatory associations of the genome with nuclear lamins provide new evidence for rhythmic spatial chromatin configurations. Nevertheless, our data suggest that periodic LADs reflect stochasticity in lamin-chromatin interactions underlying chromatin dynamics in the liver during the circadian cycle. They also argue that periodic gene expression is by and large not regulated by rhythmic chromatin associations with the nuclear lamina.

genomics↗

bioRxiv2019

Unrestrained ESCRT-III drives chromosome fragmentation and micronuclear catastrophe

The ESCRT-III membrane fission machinery1,2 restores nuclear envelope integrity during mitotic exit3,4 and interphase5,6. Whereas primary nuclei resealing takes minutes, micronuclear envelope ruptures appear irreversible and result in catastrophic collapse associated with chromosome fragmentation and rearrangements (chromothripsis), thought to be a major driving force in cancer development7-10. Despite its importance11-13, the mechanistic underpinnings of nuclear envelope sealing in primary nuclei and the defects observed in micronuclei remain largely unknown. Here we show that CHMP7, the nucleator of ESCRT-III filaments at the nuclear envelope3,14, and the inner nuclear membrane protein LEMD215 act as a compartmentalization sensor detecting the loss of nuclear integrity. In cells with intact nuclear envelope, CHMP7 is actively excluded from the nucleus to preclude its binding to LEMD2. Nuclear influx of CHMP7 results in stable association with LEMD2 at the inner nuclear membrane that licenses local polymerization of ESCRT-III. Tight control of nuclear CHMP7 levels is critical, as induction of nuclear CHMP7 mutants is sufficient to induce unrestrained growth of ESCRT-III foci at the nuclear envelope, causing dramatic membrane deformation, local DNA torsional stress, single-stranded DNA formation and fragmentation of the underlying chromosomes. At micronuclei, membrane rupture is not associated with repair despite timely recruitment of ESCRT-III. Instead, micronuclei inherently lack the capacity to restrict accumulation of CHMP7 and LEMD2. This drives unrestrained ESCRT-III recruitment, membrane deformation and DNA defects that strikingly resemble those at primary nuclei upon induction of nuclear CHMP7 mutants. Preventing ESCRT-III recruitment suppresses membrane deformation and DNA damage, without restoring nucleocytoplasmic compartmentalization. We propose that the ESCRT-III nuclear integrity surveillance machinery is a double-edged sword, as its exquisite sensitivity ensures rapid repair at primary nuclei while causing unrestrained polymerization at micronuclei, with catastrophic consequences for genome stability16-18.

cell biology↗

bioRxiv2017

Cohesin facilitates zygotic genome activation in zebrafish

At zygotic genome activation (ZGA), changes in chromatin structure are associated with new transcription immediately following the maternal-to-zygotic transition (MZT). The nuclear architectural proteins, cohesin and CCCTC-binding factor (CTCF), contribute to chromatin structure and gene regulation. We show here that normal cohesin function is important for ZGA in zebrafish. Depletion of cohesin subunit Rad21 delays ZGA without affecting cell cycle progression. In contrast, CTCF depletion has little effect on ZGA whereas complete abrogation is lethal. Genome wide analysis of Rad21 binding reveals a change in distribution from pericentromeric satellite DNA, and few locations including the miR-430 locus (whose products are responsible for maternal transcript degradation), to genes, as embryos progress through the MZT. After MZT, a subset of Rad21 binding occurs at genes dysregulated upon Rad21 depletion and overlaps pioneer factor Pou5f3, which activates early expressed genes. Rad21 depletion disrupts the formation of nucleoli and RNA polymerase II foci, suggestive of global defects in chromosome architecture. We propose that Rad21/cohesin redistribution to active areas of the genome is key to the establishment of chromosome organization and the embryonic developmental program.\n\nAuthor SummaryDuring the first few hours of existence, early zygotic cellular events are regulated by maternally inherited molecules. From a defined timepoint, the zygotic genome gradually becomes active and is transcribed. How the zygotic genome is first held inactive before becoming rapidly activated is poorly understood. Both gene repression and activation mechanisms are involved, but one aspect that has not yet been investigated is how 3-dimensional chromosome structure influences genome activation. In this study, we used zebrafish embryos to model zygotic genome activation.\n\nThe multi-subunit protein complex, cohesin, and the DNA-binding protein CCCTC-binding factor (CTCF) both have well known and overlapping roles in 3-dimensional genome organization. We depleted cohesin subunit Rad21, or CTCF, to determine their effects on zygotic genome activation. Moderate Rad21 depletion delayed transition to zygotic gene expression, without disrupting the cell cycle. By contrast, moderate CTCF depletion had very little effect; however, strong depletion of CTCF was lethal. We surveyed genome-wide binding of Rad21 before and after the zygotic genome is activated, and determined what other chromatin factors and transcription factors coincide with Rad21 binding. Before genome activation, Rad21 was located at satellite DNA and a few noncoding genes, one of which (miR-430) is responsible for degrading maternal transcripts. Following genome activation, there was a mass relocation of Rad21 to genes, particularly active genes and those that are targets of transcriptional activators when the zygotic genome is switched on. Depletion of Rad21 also affected global chromosome structure.\n\nOur study shows that cohesin binding redistributes to active RNA Polymerase II genes at the onset of zygotic gene transcription. Furthermore, we suggest that cohesin contributes to dynamic changes in chromosome architecture that occur upon zygotic genome activation.

developmental biology↗