Biology subjects

Marcon, E.

Publications and source records attributed to Marcon, E..

13 recordsLinked to original sources

bioRxiv2026

Integrative analysis reveals extensive interactions among C2H2 zinc finger proteins at chromatin loop anchors

Cys2-His2 -zinc-finger proteins (C2H2-ZFPs) form the largest class of human transcription factors, yet their potential role (s) in higher-order genome organization has remained largely poorly defined. To date, only a small number of family members, e.g., CTCF and YY1, have been shown to function in chromatin organization. Here, we examined the global relationship between C2H2-ZFPs and long-range chromatin interactions (LRIs). By integrating ChIP-seq datasets for 216 C2H2-ZFPs and genome-wide maps of chromatin looping, we observe that more than 40% of the human C2H2-ZFPs are significantly enriched at LRI anchors. We found that depletion of a subset of such C2H2-ZFPs is associated with altered expression of genes linked by the LRIs they occupy. To investigate whether protein-protein interactions (PPIs) contribute to this pattern, we generated a large-scale interactome using affinity purification followed by mass spectrometry experiments, encompassing 345 C2H2-ZFPs, and LUMIER binary interaction assays for 204 C2H2-ZFPs. We identified 1,732 binary interactions, suggesting extensive connectivity among the C2H2-ZFP family members. Integrative analysis of PPI, ChIP-seq, and chromatin interaction datasets revealed that interacting C2H2-ZFP pairs are significantly co-enriched at LRIs and frequently localize to either the same or opposing loop anchors. Finally, by correlating ChIP-seq with cancer mutational datasets, we observe that DNA-binding sites of [~]35% of LRI-associated C2H2-ZFPs overlap somatic mutations in cancer genomes. Together, our results reveal a widespread network of C2H2-ZFP interactions associated with chromatin loop anchors, providing an important resource for elucidating mechanisms regulating chromatin organization.

genomics↗

bioRxiv2025

Vaccination against H5 HP influenza virus leads to persistent immune response in wild king penguins

Since 2021, the panzootic of high pathogenicity avian influenza (HPAI) represents an increasing threat to wild vertebrate populations. In this context, recent vaccines developed for poultry could provide tools for the conservation of wild endangered birds populations. The king penguin (Aptenodytes patagonicus), a long-lived seabird breeding in dense colonies with an extended chick-rearing period, was identified as a possible surrogate species for a vaccination trial in a sub-Antarctic natural setting. We investigate here the immune response of king penguin chicks to a self-amplifying mRNA vaccine against a H5 HPAI clade 2.3.4.4b protein. Thirty chicks were vaccinated (primo- and boost-injections), 20 were kept as controls. Along 250 days of monitoring, vaccinated chicks showed a high and persistent immune response, granting a strong seroneutralisation capacity against the virus, up to fledging. No adverse effects were observed. The screening for antibodies against unspecific avian influenza viruses suggested that no natural infection occurred over the entire trial. The emergence of HPAI in the Southern Indian Ocean in October 2024 highlights the timeliness of such experimental tests. Our results show the vaccine could provide a powerful tool for mitigation and emphasises the need for studies considering ethical and practical issues of vaccination for wildlife conservation.

ecology↗

bioRxiv2025

Warming up to a new coat: moulting king penguins exhibit hyperthermia and increased peripheral heat loss

Penguins are among the most specialized thermoregulators on the planet, however, the same adaptations that maximize heat retention underwater likely hinder heat dissipation on land, possibly creating dangerous thermoregulatory challenges when encountering warming terrestrial habitats. Penguins are subject to strictly terrestrial phases, such as moulting, when metabolic heat production, insulation, and energetic constraints are heightened. We assessed thermoregulation in moulting captive king penguins (Aptenodytes patagonicus) using simultaneous measurements of core and surface temperatures to test two hypotheses. Under the thermal challenge hypothesis, an initial rise in heat dissipation effort (i.e., increased peripheral vasomotion) followed by a rise in core temperature would indicate failure to prevent hyperthermia. Under the warm-up hypothesis, an initial rise of core temperature concomitant or followed by an increase of peripheral vasomotion would indicate regulated hyperthermia, possibly to accelerate feather development. Core and surface temperatures increased drastically but concomitantly during moult, providing tentative support for the warm-up hypothesis. Moulting penguins did not pant, suggesting that peripheral heat dissipation was sufficient to regulate moulting-induced hyperthermia. Core and subcutaneous temperatures in wild individuals resembled patterns measured in captivity, despite lower heat load and additional options for behavioural thermoregulation. These results indicate that hyperthermia is prevalent in moulting king penguins, and documenting the timing of temperature changes provides novel insights for the moulting physiology of penguins. Because moulting-induced hyperthermia may contribute to heat load, we caution that moulting may increase the susceptibility of wild penguins to heat stress, especially as regions near the poles warm at a disproportionately rapid rate.

physiology↗

bioRxiv2024

Biotic interactions and environmental filtering both determine earthworm alpha and beta diversity in tropical rainforests

O_LIUnderstanding the relative importance of biotic interactions, multiple environmental drivers, and neutral processes in shaping community diversity and composition is a central question for both theoretical and applied ecology. C_LIO_LIWe analysed a dataset describing 125 earthworm communities sampled in 10 localities in French Guiana. DNA barcodes were used to delimit operational taxonomic units (OTUs) that we considered as species surrogates to avoid the taxonomic deficit and calculate community-scale species richness and pair-wise Sorensen beta-diversity. We used log-ratio and generalised linear models to highlight the effects of biotic interactions and environment as drivers of alpha diversity, and generalised dissimilarity models to figure out the relative contribution of space and environment to beta-diversity at different spatial extents. C_LIO_LICommunity-scale alpha diversity was mainly explained by habitat filtering (soil texture) and interspecific competition that limit the number of locally co-existing species. C_LIO_LIBeta diversity between pairs of communities was mainly explained by distance when comparing communities in similar habitats, by topography and available soil phosphorus when comparing communities in different habitats, and by distance, elevation and climate when comparing all possible pairs of communities. C_LIO_LIWhile community composition is determined locally by neutral processes and environmental filtering, biogeographic processes linked to dispersal limitation and adaptation to local environment are the most influential on a regional scale. This highlights the complex interplay of dispersal limitation, biotic interactions and environmental filtering during the process of community assembly. C_LI

ecology↗

bioRxiv2024

Dissecting earthworm diversity in tropical rainforests

Tropical rainforests are among the most emblematic ecosystems in terms of biodiversity. However, our understanding of the structure of tropical biodiversity is still incomplete, particularly for certain groups of soil organisms such as earthworms, whose importance for ecosystem functioning is widely recognised. This study aims at determining the relative contribution of alpha and beta components to earthworm regional diversity at a hierarchy of nested spatial scales in natural ecosystems of French Guiana. For this, we performed a hierarchical diversity partitioning of a large dataset on earthworm communities, in which DNA barcode-based operational taxonomic units (OTUs) were used as species surrogates. Observed regional diversity comprised 256 OTUs. We found that alpha diversity was lower than predicted by chance, regardless of the scale considered. Community-scale alpha diversity was on average 7 OTUs. Beta diversity among remote landscapes was higher than expected by chance, explaining as much as 87% of regional diversity. This points to regional mechanisms as the main driver of species diversity distribution in this group of organisms with low dispersal capacity. At more local scales, multiplicative beta diversity was higher than expected by chance between habitats, while it was lower than expected by chance between communities in the same habitat. This highlights the local effect of environmental filters on the species composition of communities. The calculation of a Chao 2 index predicts that as much as 1,700 species could be present in French Guiana, which represents a spectacular increase compared with available checklists, and calls into question the commonly accepted estimates of global number of earthworm species.

ecology↗

bioRxiv2024

Mind the polar sun: Solar radiations trigger frequent heat stress in breeding king penguins, despite relatively cool air temperatures.

Polar and sub-polar animals evolved to thrive in cold climates and may thus be particularly sensitive to rising temperatures associated with climate change. Penguins may be especially vulnerable, due to their dual habitat, alternating between foraging in cold waters and breeding/moulting on an increasingly warm land. Here, we characterized heat stress occurrence in breeding king penguins through behavioural observations (e.g. panting occurrence) and body temperature measurements. We observed that behavioural signs of heat stress are frequent in king penguins breeding in the sub-Antarctic region (> 20% of observations at mid-day), and that subcutaneous temperatures increase under high heat load, especially in penguins observed panting. Subcutaneous and core body temperatures were moderately correlated and both increased with heat load. Yet, their responses were not parallel since core body temperature is markedly less sensitive to heat load than subcutaneous temperature. Air temperature alone was a poor predictor of heat stress occurrence, whereas the combination of high solar radiation, low wind speed and high air temperatures provided the strongest predictive power. Finally, reproductive failures were more likely to occur on warmer days, suggesting that heat stress may have significant sublethal effects on adults that could ultimately affect population dynamics. O_FIG O_LINKSMALLFIG WIDTH=150 HEIGHT=200 SRC="FIGDIR/small/611977v3_ufig1.gif" ALT="Figure 1"> View larger version (95K): org.highwire.dtl.DTLVardef@26db91org.highwire.dtl.DTLVardef@119461dorg.highwire.dtl.DTLVardef@4a1d8forg.highwire.dtl.DTLVardef@1da9d96_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗

bioRxiv2024

A can of worms: estimating the global number of earthworm species

Estimating the overall species number for a given taxon is a central issue in ecology and conservation biology. This is especially topical for soil organisms, which comprise most known species but whose taxonomy remains largely understudied. Here, we estimated the global number of earthworm species based on the Joppa approach, which models taxonomic effort over time to estimate the total number of known and as yet unknown species in a given taxa. Our Bayesian estimation of the Joppa model suggests a global diversity of the order of 30,000 species, suggesting that the 5,679 earthworm taxa already described only represent around 20% of the actual global species diversity. However, the uncertainty around this estimate is considerable due to severe undersampling and as the model cannot unambiguously decide whether we are describing few species because of a small pool of as yet unknown species, or because of a lack of taxonomic efficiency. Considering the current rate of new species description, we calculate that it would take at least 120 years to describe all the earthworm species existing on Earth, and we discuss thedifferent strategies that should be developed to facilitate and accelerate the discovery and naming of species new to science.

ecology↗

bioRxiv2024

Recruitment of the m6A/Am demethylase FTO to target RNAs by the telomeric zinc finger protein ZBTB48

N6-methyladenosine (m6A), the most abundant internal modification on eukaryotic mRNA, and N6, 2'-O-dimethyladenosine (m6Am), are epitranscriptomic marks that function in multiple aspects of posttranscriptional regulation. Fat mass and obesity-associated protein (FTO) can remove both m6A and m6Am; however, little is known about how FTO achieves its substrate selectivity. Here, we demonstrate that ZBTB48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of ZBTB48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. ZBTB48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO- dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which ZBTB48 co-ordinates RNA- binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.

molecular biology↗

bioRxiv2023

Omicron Spike Protein Is Vulnerable to Reduction

SARS-CoV-2 virus spike (S) protein is an envelope protein responsible for binding to the ACE2 receptor, driving subsequent entry into host cells. The existence of multiple disulfide bonds in the S protein makes it potentially susceptible to reductive cleavage. Using a tri-part split luciferase-based binding assay, we evaluated the impacts of chemical reduction on S proteins from different virus variants and found that those from the Omicron family are highly vulnerable to reduction. Through manipulation of different Omicron mutations, we found that alterations in the receptor binding module (RBM) are the major determinants of this vulnerability. Specifically we discovered that Omicron mutations facilitate the cleavage of C480-C488 and C379-C432 disulfides, which consequently impairs binding activity and protein stability. The vulnerability of Omicron S proteins suggests a mechanism that can be harnessed to treat specific SARS-CoV-2 strains.

biochemistry↗

bioRxiv2021

Systematic genome-scale identification of host factors for SARS-CoV-2 infection across models yields a core single gene dependency; ACE2

SARS-CoV-2, depends on host cell components for replication, therefore the identification of virus-host dependencies offers an effective way to elucidate mechanisms involved in viral infection. Such host factors may be necessary for infection and replication of SARS-CoV-2 and, if druggable, presents an attractive strategy for anti-viral therapy. We performed genome wide CRISPR knockout screens in Vero E6 cells and 4 human cell lines including Calu-3, Caco-2, Hek293 and Huh7 to identify genetic regulators of SARS-CoV-2 infection. Our findings identified only ACE2, the cognate SARS-CoV-2 entry receptor, as a common host dependency factor across all cell lines, while all other host genes identified were cell line specific including known factors TMPRSS2 and CTSL. Several of the discovered host-dependency factors converged on pathways involved in cell signalling, lipid metabolism, immune pathways and chromatin modulation. Notably, chromatin modulator genes KMT2C and KDM6A in Calu-3 cells had the strongest impact in preventing SARS-CoV-2 infection when perturbed. Overall, the network of host factors that have been identified will be broadly applicable to understanding the impact of SARS-CoV-2 on human cells and facilitate the development of host-directed therapies. IN BRIEFSARS-CoV-2, depends on host cell components for infection and replication. Genome-wide CRISPR screens were performed in multiple human cell lines to elucidate common host dependencies required for SARS-CoV-2 infection. Only ACE2, the cognate SARS-CoV-2 entry receptor, was common amongst cell lines, while all other host genes identified were cell line specific, several of which converged on pathways involved in cell signalling, lipid metabolism, immune pathways, and chromatin modulation. Overall, a network of host factors was identified that will be broadly applicable to understanding the impact of SARS-CoV-2 on human cells and facilitate productive targeting of host genes and pathways. HIGHLIGHTS- Genome-wide CRISPR screens for SARS-CoV-2 in multiple human cell lines - Identification of wide-ranging cell-type dependent genetic dependencies for SARS-CoV-2 infection - ACE2 is the only common host factor identified across different cell types

systems biology↗

bioRxiv2021

Pharmacological targeting of a PWWP domain demonstrates cooperative control of NSD2 localization

NSD2 is the primary enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36me2), a mark associated with active gene transcription and intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two PWWP and five PHD domains believed to serve as chromatin reading modules, but their exact function in the regulation of NSD2 activity remains underexplored. Here we report a first-in-class chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 binds potently (Kd of 91 {+/-} 8 nM) to PWWP1, antagonizes its interaction with nucleosomal H3K36me2, and selectively engages endogenous NSD2 in cells. Crystal structures show that UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1 which is juxtaposed to the DNA-binding surface. In cells, UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 as a result of translocations prevalent in multiple myeloma. Mutation of other NSD2 chromatin reader domains also increases NSD2 nucleolar localization, and enhances the effect of UNC6934. Finally we identified two C-terminal nucleolar localization sequences in NSD2 that appear to drive nucleolar accumulation when one or more chromatin reader domains are disabled. These data support a model in which NSD2 chromatin engagement is achieved in a cooperative manner and subcellular localization is controlled by multiple competitive structural determinants. This chemical probe and the accompanying negative control, UNC7145, will be useful tools in defining NSD2 biology.

cell biology↗

bioRxiv2020

Functional characterization of RebL1 highlights the evolutionary conservation of oncogenic activities of the RBBP4/7 orthologue in Tetrahymena thermophila

Retinoblastoma-binding proteins 4 and 7 (RBBP4 and RBBP7) are two highly homologous human histone chaperones. They function in epigenetic regulation as subunits of multiple chromatin-related complexes and have been implicated in numerous cancers. Due to their overlapping functions, our understanding of RBBP4 and 7, particularly outside of Opisthokonts, has remained limited. Here, we report that in the ciliate protozoan Tetrahymena thermophila a single orthologue of human RBBP4 and 7 proteins, RebL1, physically interacts with histone H4 and functions in multiple epigenetic regulatory pathways. Functional proteomics identified conserved functional links associated with Tetrahymena RebL1 protein as well as human RBBP4 and 7. We found that putative subunits of multiple chromatin-related complexes including CAF1, Hat1, Rpd3, and MuvB, co-purified with RebL1 during Tetrahymena growth and conjugation. Iterative proteomics analyses revealed that the cell cycle regulatory MuvB-complex in Tetrahymena is composed of at least five subunits including evolutionarily conserved Lin54, Lin9 and RebL1 proteins. Genome-wide analyses indicated that RebL1 and Lin54 (Anqa1) bind within genic and intergenic regions. Moreover, Anqa1 targets primarily promoter regions suggesting a role for Tetrahymena MuvB in transcription regulation. RebL1 depletion decreased cellular viability and altered the expression of selected targets. Consistent with observations in glioblastoma tumors, RebL1 depletion suppressed DNA repair protein Rad51 in Tetrahymena, thus underscoring the evolutionarily conserved functions of RBBP4/7 proteins. Our results suggest the essentiality of RebL1 functions in multiple epigenetic regulatory complexes in which it impacts transcription regulation and cellular viability.

molecular biology↗

bioRxiv2020

SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and alters gene expression via direct interaction with host mRNAs

The COVID-19 pandemic has caused over one million deaths thus far. There is an urgent need for the development of specific viral therapeutics and a vaccine. SARS-CoV-2 nucleocapsid (N) protein is highly expressed upon infection and is essential for viral replication, making it a promising target for both antiviral drug and vaccine development. Here, starting from a functional proteomics workflow, we initially catalogued the protein-protein interactions of 21 SARS-CoV-2 proteins in HEK293 cells, finding that the stress granule resident proteins G3BP1 and G3BP2 copurify with N with high specificity. We demonstrate that N protein expression in human cells sequesters G3BP1 and G3BP2 through its physical interaction with these proteins, attenuating stress granule (SG) formation. The ectopic expression of G3BP1 in N-expressing cells was sufficient to reverse this phenotype. Since N is an RNA-binding protein, we performed iCLIP-sequencing experiments in cells, with or without exposure to oxidative stress, to identify the host RNAs targeted by N. Our results indicate that SARS-CoV-2 N protein binds directly to thousands of mRNAs under both conditions. Like the G3BPs stress granule proteins, N was found to predominantly bind its target mRNAs in their 3UTRs. RNA sequencing experiments indicated that expression of N results in wide-spread gene expression changes in both unstressed and oxidatively stressed cells. We suggest that N regulates host gene expression by both attenuating stress granules and binding directly to target mRNAs.

molecular biology↗