Biology subjects

Henry, L.

Publications and source records attributed to Henry, L..

17 recordsLinked to original sources

bioRxiv2026

THE MULTIFUNCTIONAL PROTEIN E4F1 REGULATES MELANOCYTIC FUNCTIONS IN MICE THROUGH PROTEIN TRANSLATION AND MITF EXPRESSION

The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of skin homeostasis, playing a critical role in epidermal stem cell maintenance and keratinocyte differentiation. However, the functions of E4F1 in other skin cell type remain poorly investigated. Here, we describe its role in melanogenesis, the physiological process for synthesis of melanin pigments. Using genetically engineered mouse models that enabled conditional inactivation of E4f1 specifically in melanocytes, we demonstrated that E4f1 loss induces severe pigmentation defects without affecting melanocyte survival nor differentiation. At the molecular level, E4f1 depletion reduces the expression of its direct transcriptional target genes involved in protein translation, including Elp3 and Eef1g, leading to translation alterations and consequently the induction of the Integrated Stress Response (ISR). This response resulted in microphthalmia-associated transcription factor (MITF) downregulation, inducing a decrease in the expression of enzymes involved in melanin synthesis. Consistent with these findings, Elp3 or Eef1g depletion recapitulated the decrease in MITF levels in vitro, and pharmacological inhibition of ISR partially rescued melanin content in vivo, confirming a key role of the E4F1-protein translation-ISR cascade in melanogenesis. Together, our data identify E4F1-associated translation functions as a key regulator of the melanocytic lineage.

physiology↗

bioRxiv2026

Deep sequencing artificially inflates estimates of microbial diversity

Sequencing artifacts challenge accuracy and reproducibility when quantifying microbial diversity. To track error propagation in microbiome analyses, we analyze no-diversity amplicons, which are amplified from host genes with limited genetic diversity or from synthetic spike-ins. We find that sequencing at greater than 104 reads exponentially increased no-diversity amplicon sequence variant (ASV) richness, with hundreds of ASVs observed per sample. This striking pattern was shared with microbial amplicons (16S rRNA, ITS, gyrB, rpoB), which revealed inflated Shannon diversity with an increase in read counts for both the community and within taxa. Comparing sequencing error profiles between no-diversity and microbial amplicons showed that truncating reads to shorter lengths and use of the AVITI Element platform can mitigate, but not abolish, the impacts of artificial inflation; we recommend caution when read depths vary orders of magnitude between samples. Overall, utilizing no-diversity amplicons can help optimize parameters to improve estimates of microbial diversity.

ecology↗

bioRxiv2026

Biotic-response networks are an important organizer of the transcriptome in wild Arabidopsis thaliana populations

Extensive laboratory experimentation has revealed conserved molecular pathways controlling growth and stress responses in plants, yet how these programs operate in natural settings remains poorly understood. We investigated transcriptome organization in wild populations of Arabidopsis thaliana by sampling plants from 60 natural sites in Europe and North America across two seasons. Transcriptomes varied extensively among individuals and showed largely continuous rather than discrete structure across geography and season. Although disease and microbial colonization were common in the wild, wild transcriptomes did not simply recapitulate canonical laboratory stress signatures. Measured microbial infection, environmental, and phenotypic variables explained only a modest fraction of total expression variation, but infection-associated signals accounted for the largest share of the explainable component. Consistent with this, biotic-response networks defined in controlled laboratory experiments were well conserved in wild transcriptomes, whereas control and abiotic-response networks were substantially reorganized. Together, these results suggest that while core transcriptional modules remain recognizable across environments, regulatory relationships among modules differ markedly between laboratory and natural contexts. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/711176v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1c89152org.highwire.dtl.DTLVardef@bcd1acorg.highwire.dtl.DTLVardef@6975a2org.highwire.dtl.DTLVardef@1a9e2fe_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2025

Metabolic plasticity supports a flexible nutritional symbiosis in Cardiocondyla ants

Nutritional symbioses have repeatedly evolved in insects, yet how hosts regulate these partnerships to balance benefits across development and environments remains unclear. Ants provide an exceptional system to address this question, as several lineages maintain ancient symbionts that can be naturally lost without harming the host. Using Cardiocondyla obscurior, which carries and occasionally loses the vertically transmitted symbiont Cand. Westeberhardia cardiocondylae, we reveal the regulatory dynamics and function of this labile association. Symbionts provide shikimate-derived nutrients that enhance colony resilience under protein limitation, while hosts actively regulate symbiont abundance during protein scarcity and cuticle formation to optimise resource allocation. In the symbionts absence, ants compensate by upregulating genes enabling tyrosine acquisition from external sources. This metabolic flexibility allows colonies to exploit symbiont-derived and environmental nutrients, sustaining both growth and survival across nutritional contexts. Our findings reveal dynamic host regulation as a mechanism sustaining the persistence and adaptability of ancient symbioses.

ecology↗

bioRxiv2024

ENTPD3-specific CAR Regulatory T cells for Local Immune Control in T1D

Despite advances in Type 1 Diabetes (T1D) management such as hybrid closed loop systems, patients still face significant morbidity, reduced life expectancy, and impaired glucose regulation compared to healthy individuals or those with pancreas transplants. Here we developed beta cell-specific Chimeric Antigen Receptors (CAR) targeting the antigen ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) using a novel cell-based phage display methodology. ENTPD3 is highly expressed on beta cells of both early and progressed T1D patients. ENTPD3 CAR regulatory T cells (Tregs) homed, expanded and persisted in pancreatic islets in a T1D mouse model (NOD) and completely prevented disease progression. Human ENTPD3 CAR Tregs displayed a stable regulatory phenotype, strong activation, and suppression. Importantly, ENTPD3 CAR T cells recognised and were fully activated by human islets. This approach holds great promise as a durable treatment option for patients with prediabetes, new-onset diabetes, or those undergoing beta cell replacement therapy.

immunology↗

bioRxiv2024

Defensive symbiont genotype distributions are linked to parasitoid attack networks

Facultative symbionts are widespread in arthropods and can provide important services such as protection from natural enemies. Yet what shapes associations with defensive symbionts in nature remains unclear. Two hypotheses suggest that either interactions with antagonists, or host plants, may explain the prevalence of symbionts through shared selective pressures and routes of horizontal transmission. Here we investigate the factors driving similarities in the Hamiltonella defensa symbiosis shared among host species within field collected aphid communities. We show that, Hamiltonellas genotype distribution strongly aligns with sharing the same parasitoids, rather than host plants, highlighting parasitoids as a key selective agent shaping the symbiosis across host species. Our data indicates parasitoid host-specificity drives the prevalence of specific aphid-Hamiltonella associations, suggesting defensive symbioses are maintained by the selective pressure imposed by dominant parasitoid species. These findings underscore the importance of interactions with natural enemies in explaining patterns of defensive symbiosis in nature.

ecology↗

bioRxiv2024

Longitudinal sequencing reveals polygenic andepistatic nature of genomic response to selection

Evolutionary adaptation to new environments likely results from a combination of selective sweeps and polygenic shifts, depending on the genetic architecture of traits under selection. While selective sweeps have been widely studied, polygenic responses are considered more prevalent but challenging to quantify. The infinitesimal model makes explicit the hypothesis about the dynamics of changes in allele frequencies under selection, where only allelic effect sizes, frequencies, linkage, and gametic disequilibrium matter. Departures from this, like long-range correlations of allele frequency changes, could be a signal of epistasis in polygenic response. We performed an Evolve & Resequence experiment in Drosophila melanogaster exposing flies to a high-sugar diet as a source of environmental stress for over 100 generations. We tracked allele frequency changes in >3000 individually sequenced flies as well as population pools and searched for loci under selection by identifying sites with allele frequency trajectories that differentiated selection regimes consistently across replicates. We estimate that at least 4% of the genome was under positive selection, the result of a highly polygenic response. Most of this response was seen as small but consistent allele frequency changes over time, and there were only a few large allele-frequency changes (selective sweeps). We then searched for signatures of selection on pairwise combinations of alleles in the new environment and found several strong signals of putative epistatic interactions across unlinked loci that were consistent across selected populations. Finally, we measured differentially expressed genes (DEGs) across treatments and show that DEGs are enriched for selected SNPs, suggesting a regulatory basis for the selective response. Our results suggest that epistatic contributions to polygenic selective response are common and lead to detectable signatures.

evolutionary biology↗

bioRxiv2022

A dynamic epibiont community associated with the bone eating worm Osedax

Osedax, the deep-sea annelid found at sunken whalefalls, is known to host Oceanospirillales bacterial endosymbionts intracellularly in specialized roots, that help it feed exclusively on vertebrate bones. Past studies, however, have also made mention of external bacteria on their trunks. During a 14-year study, we reveal a dynamic, yet persistent, succession of Campylobacterales integrated into the epidermis of Osedax, that change over time as the whale carcass degrades on the sea floor. The Campylobacterales associated with seven species of Osedax, which comprise 67% of the bacterial community on the trunk, are initially dominated by the genus Arcobacter (at early time points < 24 months), the Sulfurospirillum at intermediate stages (~ 50 months), and the Sulfurimonas at later stages (>140 months) of whale carcass decomposition. Metagenome analysis of the epibiont metabolic capabilities suggests a transition from heterotrophy to autotrophy along the successional gradient, and differences in their capacity to metabolize oxygen, carbon, nitrogen, and sulfur. Compared to free living relatives, the Osedax epibionts were highly enriched in transposable elements, implicating genetic exchange on the host surface, and contained numerous secretions systems with eukaryotic-like protein domains, suggesting a long evolutionary history with these enigmatic, yet widely distributed deep-sea worms

microbiology↗

bioRxiv2022

Latitudinal cline does not predict variation in the microbiome of wild Drosophila melanogaster

Microbiomes affect many aspects of host biology, but the eco-evolutionary forces that shape their diversity in natural populations remain poorly understood. Geographic gradients, like latitudinal clines, generate predictable patterns in biodiversity at macroecological scales, but whether these macro-scale processes apply to host-microbiome interactions is an open question. To address this question, we sampled the microbiomes of 13 natural populations of Drosophila melanogaster along a latitudinal cline in eastern United States. The microbiomes were surprisingly consistent across the cline-latitude did not predict either alpha or beta diversity. Only a narrow taxonomic range of bacteria were present in all microbiomes, indicating that strict taxonomic filtering by the host and neutral ecological dynamics are the primary factors shaping the fly microbiome. Additional temporal sampling across two independent sites revealed significant differences in microbial communities over time, suggesting that local environmental differences that vary at fine spatiotemporal scales are more likely to shape the microbiome. Our findings reveal the complexity of eco-evolutionary interactions shaping microbial variation in D. melanogaster and highlight the need for additional sampling of the microbiomes in natural populations along environmental gradients.

ecology↗

bioRxiv2021

Changes of small non-coding RNAs by severe acute respiratory syndrome coronavirus 2 infection

The ongoing pandemic of coronavirus disease 2019 (COVID-19), which results from the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a significant global public health threat, with molecular mechanisms underlying its pathogenesis largely unknown. Small non-coding RNAs (sncRNAs) are known to play important roles in almost all biological processes. In the context of viral infections, sncRNAs have been shown to regulate the host responses, viral replication, and host-virus interaction. Compared with other subfamilies of sncRNAs, including microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), tRNA-derived RNA fragments (tRFs) are relatively new and emerge as a significant regulator of host-virus interactions. Using T4 PNK-RNA-seq, a modified next-generation sequencing (NGS), we recently found that nasopharyngeal swabs (NPS) samples from SARS-CoV-2 positive and negative subjects show a significant difference in sncRNA profiles. There are about 166 SARS-CoV-2-impacted sncRNAs. Among them, tRFs are the most significantly affected and almost all impacted tRFs are derived from the 5-end of tRNAs (tRF5). Using a modified qRT-PCR, which was recently developed to specifically quantify tRF5s by isolating the tRF signals from its corresponding parent tRNA signals, we validated that tRF5s derived from tRNA GluCTC (tRF5-GluCTC), LysCTT (tRF5-LysCTT), ValCAC (tRF5-ValCAC), CysGCA (tRF5-CysGCA) and GlnCTG (tRF5-GlnCTG) are enhanced in NPS samples of SARS-CoV2 patients and SARS-CoV2-infected airway epithelial cells. In addition to host-derived ncRNAs, we also identified several sncRNAs derived from the virus (svRNAs), among which a svRNA derived from CoV2 genomic site 346 to 382 (sv-CoV2-346) has the highest expression. The induction of both tRFs and sv-CoV2-346 has not been reported previously, as the lack of the 3-OH ends of these sncRNAs prevents them to be detected by routine NGS. In summary, our studies demonstrated the involvement of tRFs in COVID-19 and revealed new CoV2 svRNAs.

microbiology↗

bioRxiv2021

Synergistic Phase Separation of Two Pathways Promotes Integrin Clustering and Integrin Adhesion Complex Formation

Integrin adhesion complexes (IACs) are integrin-based plasma membrane-associated compartments where cells sense environmental cues. The physical mechanisms and molecular interactions that mediate nascent IAC formation are unclear. We found that both p130Cas ("Cas") and Focal adhesion kinase ("FAK") undergo liquid-liquid phase separation in vitro under physiologic conditions. Cas- and FAK- driven phase separation is sufficient to reconstitute kindlin-dependent integrin clustering in vitro. In vitro condensates and cellular IACs exhibit similar sensitivities to environmental perturbations including changes in temperature and pH. Furthermore, mutations that inhibit or enhance phase separation in vitro reduce or increase the number of IACs in cells, respectively. Finally, we find that the Cas and FAK pathways act synergistically to promote phase separation, integrin clustering and IAC formation in vitro and in cells. We propose that Cas- and FAK- driven phase separation provides an intracellular trigger for integrin clustering and nascent IAC formation.

cell biology↗

bioRxiv2020

Exosomal melanotransferrin as a potential biomarker for metastatic melanoma

Cutaneous melanoma is the most lethal type of skin cancer. Early detection is crucial to improve the outcome of melanoma patients. The identification of noninvasive prognostic biomarkers for the follow-up of melanoma patients is still in demand for clinical use. We show here that exosomal melanotransferrin (MTf) fulfils the biomarker characteristics required to meet this demand. MTf is typically overexpressed in melanoma cells compared to other cell types - including cancer cells - and is efficiently sorted and secreted with nanovesicles, or so-called exosomes, due to its membrane-anchoring by a glycosylphosphatidylinositol. MTf is exposed on the surface of exosomes and is accessible for antibody recognition. An ELISA was set-up to quantify MTf after immobilization of nanovesicles through the exosomal constituent tetraspanins CD63. MTf was detected using low number of exosomes purified from melanoma cell line cultures, and MTf detection was abolished by phosphatidylinositol-specific phospholipase C (PI-PLC) treatment. This exosomal MTf ELISA was able to discriminate an equal number of assayed exosomes purified from two different melanoma cell lines (A-375 vs SK-MEL-28). Moreover, plasma samples from patients with melanoma and noncancer disease were assayed using this ELISA and exosomal MTf was validated as a potential melanoma biomarker.

cell biology↗

bioRxiv2020

GxGxE interactions and adaptive potential of the microbiome in Drosophila melanogaster

Can the microbiome serve as a reservoir of adaptive potential for hosts? To address this question, we leveraged [~]150 generations of experimental evolution in Drosophila melanogaster in a stressful, high-sugar (HS) diet. We performed a fully reciprocal transplant experiment using the control and evolved HS bacteria. If the microbiome confers benefits to hosts, then transplant recipients should gain fitness benefits compared to controls. Interestingly, we found that benefits do exist, but mismatches between fly evolution and microbiome exerted fitness costs by slowing development and reducing fecundity, especially in the stressful HS diet. The dominant HS bacteria (Acetobacter pasteurianus) uniquely encoded several genes to enable uric acid degradation, mediating the toxic effects of uric acid accumulation due to the HS diet for flies. Our study demonstrates that host genotype x microbiome x environment interactions have substantial effects on host phenotype, highlighting how host evolution and ecological context together shape the adaptive potential of the microbiome.

evolutionary biology↗

bioRxiv2020

A Novel CD206 Targeting Peptide Inhibits Bleomycin Induced Pulmonary Fibrosis in Mice

Activated M2 polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios such as Acute Respiratory Disease Syndrome (ARDS) and Idiopathic Pulmonary Fibrosis (IPF), through the production of inflammatory and fibrosis-inducing cytokines. In this study, we investigated the effect of targeting the CD206 receptor with a novel fragment of a Host Defense Peptide (HDP), RP-832c to decrease cytokines that cause fibrosis. RP-832c selectively binds to CD206 on M2 polarized bone marrow derived macrophages (BMDM) in vitro, resulting in a time-dependent decrease in CD206 expression, and a transient increase in M1 marker TNF, which resolves over a 24hr period. To elucidate the antifibrotic effect of RP-832c, we used a murine model of bleomycin (BLM) -induced early-stage pulmonary fibrosis. RP-832c significantly reduced bleomycin-induced fibrosis in a dosage dependent manner, as well as decreased CD206, TGF-{beta}1 and -SMA expression in mouse lungs. Interestingly we did not observe any changes in the resident alveolar macrophage marker CD170 expression. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased fibrosis in the lung, as well as significantly decreased inflammatory cytokines TNF, IL-6, IL-10, INF-{gamma}, CXCL1/2, and fibrosis markers TGF-{beta}1 and MMP-13. In comparison with FDA approved drugs, Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed on body weight or blood chemistry. In summary, RP-832c is a potential agent to mitigate the overactivity of M2 macrophages in pathogenesis several pulmonary fibrotic diseases, including SARS-CoV-2 induced lung fibrosis.

pathology↗

bioRxiv2019

The primary structural photoresponse of phytochrome proteins captured by a femtosecond X-ray laser

Phytochrome proteins control the growth, reproduction, and photosynthesis of plants, fungi, and bacteria. Light is detected by a bilin cofactor, but it remains elusive how this leads to activation of the protein through structural changes. We present serial femtosecond X-ray crystallographic data of the chromophore-binding domains of a bacterial phytochrome at delay times of 1 ps and 10 ps after photoexcitation. The structures reveal a twist of the D-ring, which lead to partial detachment of the chromophore from the protein. Unexpectedly, the conserved so-called pyrrole water is photodissociated from the chromophore, concomitant with movement of the A-ring and a key signalling aspartate. The changes are wired together by ultrafast backbone and water movements around the chromophore, channeling them into signal transduction towards the output domains. We suggest that the water dissociation is key to the phytochrome photoresponse, explaining the earliest steps of how plants, fungi and bacteria sense red light.

biophysics↗

bioRxiv2019

Can the microbiome influence host evolutionary trajectories?

The microbiome shapes many traits in hosts, but we still do not understand how it influences host evolution. To impact host evolution, the microbiome must be heritable and have phenotypic effects on the host. However, the complex inheritance and context-dependence of the microbiome challenges traditional models of organismal evolution. Here, we take a multifaceted approach to identify conditions in which the microbiome influences host evolutionary trajectories. We explore quantitative genetic models to highlight how microbial inheritance and phenotypic effects can modulate host evolutionary responses to selection. We synthesize the literature across diverse taxa to find common scenarios of microbiome driven host evolution. First, hosts may leverage locally adapted microbes, increasing survivorship in stressful environments. Second, microbial variation may increase host phenotypic variation, enabling exploration of novel fitness landscapes. We further illustrate these effects by performing a meta-analysis of artificial selection in Drosophila, finding that bacterial diversity also frequently responds to host selection. We conclude by outlining key avenues of research and experimental procedures to improve our understanding of the complex interplay between hosts and microbiomes. By synthesizing perspectives through multiple conceptual and analytical approaches, we show how microbiomes can influence the evolutionary trajectories of hosts.

evolutionary biology↗

bioRxiv2018

MicroRNA-202 (miR-202) controls female fecundity by regulating medaka oogenesis

Female gamete production relies on coordinated molecular and cellular processes that occur in the ovary throughout oogenesis. In fish, as in other vertebrates, these processes have been extensively studied both in terms of endocrine/paracrine regulation and protein expression and activity. The role of small non-coding RNAs in the regulation of animal reproduction remains however largely unknown and poorly investigated, despite a growing interest for the importance of miRNAs in a wide variety of biological processes. Here, we analyzed the role of miR-202, a miRNA predominantly expressed in male and female gonads in several vertebrate species. We studied its expression in the medaka ovary and generated a mutant line (using CRISPR/Cas9 genome engineering) to determine its importance for reproductive success with special interest for egg production. Our results show that miR-202-5p is the biologically active form of the miRNA and that it is expressed in granulosa cells and in the unfertilized egg. The knock out (KO) of miR-202 resulted in a strong phenotype both in terms of number and quality of eggs produced. Mutant females exhibited either no egg production or produced a drastically reduced number of eggs that could not be fertilized, ultimately leading to no reproductive success. We quantified the size distribution of the oocytes in the ovary of KO females and performed a genome-wide transcriptomic analysis approach to identified dysregulated molecular pathways. Together, cellular and molecular analyses indicate that lack of miR-202 impairs the early steps of oogenesis/folliculogenesis and decreases the number of large (i.e. vitellogenic) follicles, ultimately leading to dramatically reduced female fecundity. This study sheds new light on the regulatory mechanisms that control the early steps of follicular development and provides the first in vivo functional evidence that an ovarian-predominant microRNA may have a major role in female reproduction.\n\nAuthor summaryThe role of small non-coding RNAs in the regulation of animal reproduction remains poorly investigated, despite a growing interest for the importance of miRNAs in a wide variety of biological processes. Here, we analyzed the role of miR-202, a miRNA predominantly expressed in gonads in vertebrate. We studied its expression in the medaka ovary and knocked out the miR-202 genes to study its importance for reproductive success. We showed that the lack of miR-202 results in the sterility of both females and males. In particular, it lead to a drastic reduction of both the number and the quality of eggs produced by females. Mutant females exhibited either no egg production or produced a drastically reduced number of eggs that could not be fertilized, ultimately leading to no reproductive success. Quantitative histological and molecular analyses indicated that miR-202 KO impairs oocyte development and is also associated with the dysregulation of many genes that are critical for reproduction. This study sheds new light on the regulatory mechanisms that control oogenesis and provides the first in vivo functional evidence that an ovarian-predominant microRNA may have a major role in female reproduction.

genetics↗