Biology subjects

Morin, M.

Publications and source records attributed to Morin, M..

9 recordsLinked to original sources

bioRxiv2025

Microtubule deacetylation drives kinesin-1 mediated mitochondrial transport accelerating breast cancer cell migration

Mitochondrial trafficking is reprogrammed in metastatic breast cancer cells to sustain their migratory and invasive behavior. Mitochondria repositioning to sites of high energy demand is governed by a balance between opposing dynein and kinesin-1 (KIF5B) molecular motors whose regulation remains incompletely understood. Here, we identify the SYBU gene as a candidate prognostic marker downregulated in metastatic disease. SYBU encodes syntabulin, a mitochondria outer membrane protein that interacts with dynein to counterbalance KIF5B-dependent anterograde transport to the cell cortex. Loss of SYBU disrupts the balance, causing excessive KIF5B-driven mitochondria movement, microtubule damage and deacetylation. In turn, microtubule deacetylation reinforces KIF5B-mediated transport, creating a positive feedback loop that drives mitochondria distribution close to the cell periphery and enhances cancer cell migration. Pharmacological inhibition of the tubulin deacetylase HDAC6 restores mitochondrial positioning and reduces cell migration in SYBU-deficient cells. Our findings identify SYBU as a key regulator of mitochondrial trafficking and pave the way to personalized therapeutic approaches for metastatic breast tumors with low SYBU expression.

cell biology↗

bioRxiv2024

Pathological mechanisms and candidate therapeutic approaches in the hearing loss of mice carrying human MIR96 mutations

Progressive hearing loss is a common problem in the human population with no effective therapeutics currently available. However, it has a strong genetic contribution, and investigating the genes and regulatory interactions underlying hearing loss offers the possibility of identifying therapeutic candidates. Mutations in regulatory genes are particularly useful for this, and an example is the microRNA miR-96, a transcriptional regulator which controls hair cell maturation. Mice and humans carrying mutations in Mir96 all develop hearing loss, but different mutations result in different physiological, structural and transcriptional phenotypes. Here we present our characterisation of two lines of mice carrying different human mutations knocked-in to Mir96. While mice homozygous for either mutation are profoundly deaf from two weeks old, the heterozygous phenotypes differ markedly, with only one mutation resulting in hearing impairment in heterozygosis. Investigations of the structural phenotype showed that one mutation appears to lead to synaptic defects, while the other has a much more severe effect on the hair cell stereociliary bundles. Transcriptome analyses revealed a wide range of misregulated genes in both mutants which were notably dissimilar. We used the transcriptome analyses to investigate candidate therapeutics, and tested one, finding that it delayed the progression of hearing loss in heterozygous mice. Our work adds further support for the importance of the gain of novel targets in microRNA mutants, and offers a proof of concept for the identification of pharmacological interventions to maintain hearing.

genetics↗

bioRxiv2023

Seasonal tissue-specific gene expression reveals reproductive and stress-related transcriptional systems in wild crown-of-thorns starfish

Animals are influenced by the season, yet we know little about the changes that occur in most species throughout the year. This is particularly true in tropical marine animals that experience relatively small annual temperature and daylight changes. Like many coral reef inhabitants, the crown-of-thorns starfish (COTS), well known as a notorious consumer of corals and destroyer of coral reefs, reproduces exclusively in the summer. By comparing gene expression in seven somatic tissues procured from wild COTS sampled on the Great Barrier Reef, we identified more than 2,000 protein-coding genes that change significantly between summer and winter. COTS genes that appear to mediate conspecific communication - including both signalling factors released into the surrounding sea water and cell surface receptors - are upregulated in external secretory and sensory tissues in the summer, often in a sex-specific manner. The sexually dimorphic gene expression appears to be underpinned by sex- and season-specific transcription factors (TFs) and gene regulatory programs. There are over 100 TFs that are seasonally expressed, 86% of which are significantly upregulated in the summer. Six nuclear receptors are upregulated in all tissues in the summer, suggesting that systemic seasonal changes are hormonally controlled, as occurs in vertebrates. Unexpectedly, there is a suite of stress-related chaperone proteins and TFs, including HIF, ATF3, C/EBP, CREB and NF-{kappa}B, that are uniquely co-expressed in gravid females. The upregulation of these stress proteins in the summer suggests the demands of oogenesis in this highly fecund starfish affects protein stability and turnover in somatic cells. Together, these circannual changes in COTS gene expression provide novel insights into seasonal changes in this coral reef pest and have the potential to identify vulnerabilities for targeted biocontrol.

zoology↗

bioRxiv2023

O-antigen biosynthesis mediates evolutionary trade-offs within a simple community

Diverse populations of bacteriophages infect and co-evolve with their bacterial hosts. Although host recognition and infection occurs within microbiomes, the molecular mechanisms underlying host-phage interactions within a community context remain poorly studied. The biofilms (rinds) of aged cheeses contain taxonomically diverse microbial communities that follow reproducible growth patterns and can be manipulated under laboratory conditions. In this study, we use cheese as a model for studying phage-microbe interactions by identifying and characterising a tractable host-phage pair co-occurring within a model Brie community. We isolated novel bacteriophage TS33 that kills Hafnia sp. JB232 (hereafter Hafnia), a member of the model community. TS33 is easily propagated in the lab and naturally co-occurs in the cheese with the Brie community, rendering it a prime candidate for the study of host-phage interactions. We performed growth assays of the Hafnia, TS33 and the fungal community members, Geotrichum candidum and Penicillium camemberti. Employing Random Barcode Transposon Sequencing (RB-TnSeq) experiments, we identified candidate host factors that contribute to TS33 infectivity, many of which are critical to the integrity of bacterial O-antigen. Notably, disruption of these genes results in decreased susceptibility to infection by phage TS33, while simultaneously exhibiting a significant negative effect on the fitness of Hafnia in the presence of the fungi. Therefore, O-antigen mutations may have pleiotropic effects on the interactions between Hafnia and the rest of the Brie community. Ongoing and future studies aim to unearth the molecular mechanisms by which the O-antigen of Hafnia mediates its interactions with its viral and fungal partners.

microbiology↗

bioRxiv2023

Metabolomics of bacterial-fungal pairwise interactions reveal conserved molecular mechanisms

Bacterial-fungal interactions (BFIs) can shape the structure of microbial communities, but the small molecules mediating these BFIs are often understudied. We explored various optimization steps for our microbial culture and chemical extraction protocols for bacterial-fungal co-cultures, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed that metabolomic profiles are mainly comprised of fungi derived features, indicating that fungi are the key contributors to small molecule mediated BFIs. LC-inductively coupled plasma MS (LC-ICP-MS) and MS/MS based dereplication using database searching revealed the presence of several known fungal specialized metabolites and structurally related analogues in these extracts, including siderophores such as desferrichrome, desferricoprogen, and palmitoylcoprogen. Among these analogues, a novel putative coprogen analogue possessing a terminal carboxylic acid motif was identified from Scopulariopsis spp. JB370, a common cheese rind fungus, and its structure was elucidated via MS/MS fragmentation. Based on these findings, filamentous fungal species appear to be capable of producing multiple siderophores with potentially different biological roles (i.e. various affinities for different forms of iron). These findings highlight that fungal species are important contributors to microbiomes via their production of abundant specialized metabolites and their role in complex communities should continue to be a priority.

microbiology↗

bioRxiv2022

Crown-of-thorns starfish in captivity experience sustained large-scale changes in gene expression

Marine animals in the wild are often difficult to access, so that biologists have to extrapolate from the study of animals in captivity. However, the implicit assumption that physiological and cellular processes of animals in artificial environments are not significantly different from those in the wild has rarely been tested. Here we investigate the extent to which the biological state of an animal is impacted by captivity by comparing global gene expression in wild and captive crown-of-thorns starfish (COTS). We compare transcriptomes of three external tissues obtained from wild COTS with captive COTS maintained in aquaria for at least one week. On average, an astonishingly large 24% of the coding sequences in the genome are differentially expressed. Comparing transcriptomes from coelomocytes - cells in internal coelomic fluid - in wild and captive COTS, we find that 20% of the coding sequences in the genome rapidly change expression. These captive transcriptomes remained markedly different from the wild ones for more than 30 days in captivity, and showed no indication of reverting back to a wild state. Genes consistently upregulated in captivity include those involved in oxidative stress and energy metabolism, whereas genes downregulated are involved in intercellular signalling. These extensive changes in gene expression in captive COTS suggest that captivity has a profound and sustained impact on the physiology, behaviour and health of these echinoderms. The potential for such dramatic changes should be accounted for when designing studies seeking to understand wild animals.

molecular biology↗

bioRxiv2022

Evolution of CRISPR-associated Endonucleases as Inferred from Resurrected Proteins

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 protein is an effector that plays a major role in a prokaryotic adaptive immune system, by which invading DNA can be targeted and cut for inactivation. The Cas9 endonuclease is directed to target sites by a guide RNA (gRNA) where Cas9 can recognize specific sequences (PAMs) in foreign DNA, which then serve as an anchoring point for cleavage of the adjacent RNA-matching DNA region. Although the CRISPR-Cas9 system has been widely studied and repurposed for diverse applications (notably, genome editing), its origin and evolution remain to be elucidated. Here, we investigate the evolution of Cas9 from resurrected ancient nucleases (anCas) in extinct firmicutes species as old as 2600 myr to the current day. Surprisingly, we demonstrate that these ancient forms were much more flexible in their PAM and gRNA scaffold requirements compared to modern day Cas9 enzymes. In addition, anCas portrays a gradual paleoenzymatic adaptation from nickase to double-strand break activity, suggesting a mechanism by which ancient CRISPR systems could propagate when harboring Cas enzymes with minimal PAMs. The oldest anCas also exhibit high levels of activity with ssDNA and ssRNA targets, resembling Cas nucleases in related system types. Finally, we illustrate editing activity of the anCas enzymes in human cells. The prediction and characterization of anCas proteins uncovers an unexpected evolutionary trajectory leading to ancient enzymes with extraordinary properties.

evolutionary biology↗

bioRxiv2020

From iron to antibiotics: Identification of conserved bacterial-fungal interactions across diverse partners

Microbial interactions are major determinants in shaping microbiome structure and function. Although fungi are found across diverse microbiomes, the mechanisms through which fungi interact with other species remain largely uncharacterized. In this work, we explore the diversity of ways in which fungi can impact bacteria by characterizing interaction mechanisms across 16 different bacterial-fungal pairs, involving 8 different fungi and 2 bacteria (Escherichia coli and Pseudomonas psychrophila). Using random barcode transposon-site sequencing (RB-TnSeq), we identified a large number of bacterial genes and pathways important in fungal interaction contexts. Within each interaction, fungal partners elicit both antagonistic and beneficial effects. Using a panel of phylogenetically diverse fungi allowed us to identify interactions that were conserved across all species. Our data show that all fungi modulate the availability of iron and biotin, suggesting that these may represent conserved bacterial-fungal interactions. Several fungi also appear to produce previously uncharacterized antibiotic compounds. Generating a mutant in a master regulator of fungal secondary metabolite production showed that fungal metabolites are key shapers of bacterial fitness profiles during interactions. This work demonstrates a diversity of mechanisms through which fungi are able to interact with bacterial species. In addition to many species-specific effects, there appear to be conserved interaction mechanisms which may be important across microbiomes.

microbiology↗

bioRxiv2018

Changes in the genetic requirements for microbial interactions with increasing community complexity

Microbial community structure and function rely on complex interactions whose underlying molecular mechanisms are poorly understood. To investigate these interactions in a simple microbiome, we introduced E. coli into an experimental community based on a cheese rind and identified the differences in E. colis genetic requirements for growth in interactive and non-interactive contexts using Random Barcode Transposon Sequencing (RB-TnSeq) and RNASeq. E. colis genetic requirements varied among pairwise growth conditions and between pairwise and community conditions. Our analysis points to mechanisms by which growth conditions change as a result of increasing community complexity and suggests that growth within a community relies on a combination of pairwise and higher order interactions. Our work provides a framework for using the model organism E. coli as a probe to investigate microbial interactions regardless of the genetic tractability of members of the studied ecosystem.

microbiology↗