Biology subjects

Dilworth, J.

Publications and source records attributed to Dilworth, J..

11 recordsLinked to original sources

bioRxiv2025

Morphological plasticity in a reef-building coral is context-dependent and trades off with resistance to thermal stress

In sessile, long-lived organisms, such as reef-building corals, phenotypic plasticity may play a key role in mitigating the impacts of climate change. Plasticity is often context-dependent and has costs and limits, ultimately resulting in adaptive, neutral, or maladaptive effects. However, our understanding of the mechanisms that maintain variation in, and therefore drive the evolution of, plasticity is still limited. We use a field-based transplant experiment to show context-dependent tradeoffs to morphological plasticity in Acropora cervicornis under real-world conditions driven by climate change. We find that while morphological plasticity is neutral under some conditions, it trades off with thermal tolerance during moderate temperature stress during a marine heatwave. Additionally, we find that plasticity changes over time, underlining the importance of its temporal dynamics in long-lived organisms. Our results demonstrate a key role for environmental change in the eco-evolutionary dynamics of plasticity by demonstrating context-dependent costs under real-world thermal stress.

evolutionary biology↗

bioRxiv2024

SMCHD1 activates the expression of genes required for the expansion of human myoblasts

SMCHD1 is an epigenetic regulatory protein known to modulate the targeted repression of large chromatin domains. Diminished SMCHD1 function in muscle fibers causes Facioscapulohumeral Muscular Dystrophy (FSHD2) through derepression of the D4Z4 chromatin domain, an event which permits the aberrant expression of the disease-causing gene DUX4. Given that SMCHD1 plays a broader role in establishing the cellular epigenome, we examined whether loss of SMCHD1 function might affect muscle homeostasis through additional mechanisms. Here we show that acute depletion of SMCHD1 results in a DUX4-independent defect in myoblast proliferation. Genomic and transcriptomic experiments determined that SMCHD1 associates with enhancers of genes controlling cell cycle to activate their expression. Amongst these cell cycle regulatory genes, we identified LAP2 as a key target of SMCHD1 required for the expansion of myoblasts, where the ectopic expression of LAP2 rescues the proliferation defect of SMCHD1-depleted cells. Thus, the epigenetic regulator SMCHD1 can play the role of a transcriptional co-activator for maintaining the expression of genes required for muscle progenitor expansion. This DUX4-independent role for SMCHD1 in myoblasts suggests that the pathology of FSHD2 may be a consequence of defective muscle regeneration in addition to the muscle wasting caused by spurious DUX4 expression. Chromatin modifier SMCHD1 regulates the proliferation of human myoblasts SMCHD1 binds to enhancers of cell cycle regulatory genes to activate their expression Lap2 is an SMCHD1 direct target gene that regulates the expansion of human myoblasts.

cell biology↗

bioRxiv2023

Self-renewing Sox9+ osteochondral stem cells in the postnatal skeleton

Postnatal skeletal growth, homeostatic maintenance, and regeneration is driven by skeletal stem cells. In addition, it is well established that skeletal tissues lose their regenerative potential with age, comorbidities, and repeated trauma, possibly through stem cell exhaustion or loss of function. However, it is largely unknown where these cells reside in skeletal tissues, what molecular mechanisms regulate their self-renewal and fate decisions, and how to isolate, purify, and expand them ex vivo. Therefore, there is an urgent need for a deeper understanding of postnatal skeletal stem cells. Here, we used genetic lineage tracing, thymidine analogues retention, whole bone microscopy, imaging cytometry, in vitro assays, and single cell transcriptomics and provide the first experimental evidence for the existence of self-renewing osteochondral stem cells in the postnatal skeleton in both males and females. We also show direct comparisons between adult, fetal, mouse, and human skeletal stem cells at the transcriptome level.

developmental biology↗

bioRxiv2023

Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating JMJD3

Stains are known to be anti-inflammatory, but the mechanism remains poorly understood. Here we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NF{kappa}B and Jmjd3 expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statins in vitro or isolated from statin-treated mice in vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.

biochemistry↗

bioRxiv2022

Fine-scale variability in coral bleaching and mortality during a marine heatwave

Coral bleaching and mortality can show significant spatial and taxonomic heterogeneity at local scales, highlighting the need to understand the fine-scale drivers and impacts of thermal stress. In this study, we used structure-from-motion photogrammetry to track coral bleaching, mortality, and changes in community composition during the 2019 marine heatwave in K[a]ne ohe Bay, Hawai i. We surveyed 30 shallow reef patches every 3 weeks for the duration of the bleaching event (August-December) and one year after, resulting in a total of 210 large-area, high-resolution photomosaics that enabled us to follow the fate of thousands of coral colonies through time. We also measured environmental variables such as temperature, sedimentation, depth, and wave velocity at each of these sites, and extracted estimates of habitat complexity (rugosity R and fractal dimension D) from digital elevation models to better understand their effects on patterns of bleaching and mortality. We found that up to 80% of corals experienced moderate to severe bleaching in this period, with peak bleaching occurring in October when heat stress (DHW) reached its maximum. Mortality continued to accumulate as bleaching levels dropped, driving large declines in more heat-susceptible species (77% loss of Pocillopora cover) and moderate declines in heat-tolerant species (19% and 23% for Porites compressa and Montipora capitata, respectively). Declines in live coral were accompanied by a rapid increase in algal cover across the survey sites. Spatial differences in bleaching were significantly linked to habitat complexity and coral species composition, with reefs that were dominated by Pocillopora experiencing the most severe bleaching. Mortality was also influenced by species composition, fractal dimension, and site-level differences in thermal stress. Our results show that spatial heterogeneity in the impacts of bleaching are driven by a mix of environmental variation, habitat complexity, and differences in assemblage composition.

ecology↗

bioRxiv2022

Reducing Cholesterol in Resting Macrophage Activates NF-kB through Mitochondria, Resulting in Epigenomic Reprogramming to Dampen Inflammation in Activated Macrophages

Cholesterol plays an important role in macrophage functions including their immune response1. Recently, NF-kB was shown to reprogram the epigenome in macrophages2. Here, we show that NF-kB pathway is activated in resting macrophages when cholesterol is reduced by statin or methyl-{beta}-cyclodextrin (MCD). Activated NF-kB increases the expression of histone-modifying enzymes, such as demethylase JMJD3. We provide evidence that the epigenome in these macrophages is reprogrammed, likely driven by NF-kB and histone modifications2. We also show that cholesterol reduction in macrophages results in suppression of mitochondria respiration. Specifically, cholesterol levels in the inner membrane of the mitochondria is reduced, which impairs the efficiency of ATP synthase (complex V). Consequently, protons accumulate in the intermembrane space to active NF-kB and JMJD3, thereby modifying the epigenome. When subsequently challenged by the inflammatory stimulus lipopolysaccharide (LPS), cholesterol-reduced macrophages generate responses that are less pro-inflammatory and more homeostatic, which should favour inflammation resolution. Taken together, we describe a mechanism by which the level of mitochondrial cholesterol in resting macrophages regulates the epigenome through NF-kB, thereby preparing macrophage for future immune activation.

cell biology↗

bioRxiv2021

A fast Myh super enhancer dictates adult muscle fiber phenotype through competitive interactions with the fast Myh genes

The contractile properties of adult myofibers are shaped by their Myosin heavy chain (MYH) isoform content. We identify by snATAC-seq a 42kb super-enhancer (SE) at the locus regrouping the fast Myh (fMyh) genes. By 4C-seq we show that active fMyh promoters interact with the SE by DNA looping, leading to the activation of a single promoter per nucleus. A rainbow mouse transgenic model of the locus including the SE recapitulates the endogenous spatio-temporal expression of adult fMyh genes. In situ deletion of the SE by CRISPR/Cas9 editing demonstrates its major role in the control of associated fMyh genes, and deletion of two fMyh genes at the locus reveals an active competition of the promoters for the shared SE. Last, by disrupting the organization of fMyh, we uncover positional heterogeneity within limb skeletal muscles that may underlie selective muscle susceptibility to damage in certain myopathies.

cell biology↗

bioRxiv2020

Host genotype and stable differences in algal symbiont communities explain patterns of thermal stress response of Montipora capitata following thermal pre-exposure and across multiple bleaching events

As sea surface temperatures increase worldwide due to climate change, coral bleaching events are becoming more frequent and severe, resulting in reef degradation. Leveraging the inherent ability of reef-building corals to acclimatize to thermal stress via pre-exposure to protective temperature treatments may become an important tool in improving the resilience of coral reefs to rapid environmental change. We investigated whether historical bleaching phenotype, coral host genotype, and exposure to protective temperature treatments would affect the response of the Hawaiian coral Montipora capitata to natural thermal stress. Fragments were collected from colonies that demonstrated different bleaching responses during the 2014-2015 event in K[a]neohe Bay (Oahu, Hawaii) and exposed to four different artificial temperature pre-treatments (and a control at ambient temperature). After recovery, fragments experienced a natural thermal stress event either in laboratory conditions or their native reef environment. Response to thermal stress was quantified by measuring changes in the algal symbionts photochemical efficiency, community composition, and relative density. Historical bleaching phenotype was reflected in stable differences in symbiont community composition, with historically bleached corals containing only Cladocopium symbionts and historically non-bleached corals having mixed symbiont communities dominated by Durusdinium. Mixed-community corals lost more Cladocopium than Cladocopium-only corals during the natural thermal stress event, and preferentially recovered with Durusdinium. Laboratory pre-treatments exposed corals to more thermal stress than anticipated, causing photochemical damage that varied significantly by genotype. While none of the treatments had a protective effect, temperature variation during treatments had a significant detrimental effect on photochemical efficiency during the thermal stress event. These results show that acclimatization potential is affected by fine-scale differences in temperature regime, host genotype, and relatively stable differences in symbiont community composition that underpin historical bleaching phenotypes in M. capitata.

ecology↗

bioRxiv2020

Metabolomic signatures of coral bleaching history

Coral bleaching, a process where corals expel their photosynthetic symbionts, has a profound impact on the health and function of coral reefs. As global ocean temperatures continue to rise, bleaching poses the greatest threat to coral reef ecosystems. Here, untargeted metabolomics was used to analyze the biochemicals in pairs of adjacent corals from a patch reef in K[a]ne ohe Bay, Hawai i, where one colony in the pair bleached (in 2015) and recovered while the other did not bleach. There was a strong metabolomic signature of prior bleaching history four years after recovery found in both the host and its algal symbionts. Machine learning analysis determined that the strongest metabolite drivers of the difference in bleaching phenotype were a group of betaine lipids. Those with saturated fatty acids were significantly enriched in thermally tolerant corals and those with longer, unsaturated and diacyl forms were enriched in historically bleached corals. Host immune response molecules, Lyso-PAF and PAF, were also altered by bleaching history and were strongly correlated with symbiont community and algal-derived metabolites suggesting a role of coral immune modulation in symbiont choice and bleaching response. To validate these findings, we tested a separate in situ set of corals and were able to predict the bleaching phenotype with 100% accuracy. Furthermore, corals subjected to an experimental temperature stress had strong phenotype-specific responses in all components of the holobiont, which served to further increase the differences between historical bleaching phenotypes. Thus, we show that natural bleaching susceptibility is simultaneously manifested in the biochemistry of the coral animal and the algal symbiont and that this bleaching history results in different physiological responses to temperature stress. This work provides insight into the biochemical mechanisms involved in coral bleaching and presents a valuable new tool for resilience-based reef restoration.

ecology↗

bioRxiv2019

Chromatin reorganization during myoblast differentiation involves the caspase-dependent removal of SATB2

Induction of lineage-specific gene programs are strongly influenced by alterations in local chromatin architecture. However, key players that impact this genome reorganization remain largely unknown. Here, we report that removal of special AT-rich binding protein 2 (SATB2), a nuclear protein that binds matrix attachment regions, is a key event in initiating myogenic differentiation. Deletion of SATB2 in muscle cell culture models and in vivo, accelerates differentiation and depletes the muscle progenitor pool, respectively. Genome wide analysis indicates that SATB2 binding is both repressive and inductive, as loss of SATB2 leads to expression of differentiation regulatory factors and inhibition of genes that impair this process. Finally, we noted that the differentiation-specific decline in SATB2 protein is dependent on a caspase 7-mediated cleavage event. Taken together, this study demonstrates that temporal control of SATB2 protein is critical for shaping the chromatin environment and coordinating the myogenic differentiation program. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/883579v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@12ca82corg.highwire.dtl.DTLVardef@d50a56org.highwire.dtl.DTLVardef@99ba7borg.highwire.dtl.DTLVardef@a216e3_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

molecular biology↗

bioRxiv2018

A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling

Bromodomains (BRDs) are evolutionary conserved epigenetic protein interaction modules which recognize (\"read\") acetyl-lysine, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective tool small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan(R) and demonstrate the utility of the set using studies of muscle cell differentiation and triple negative breast cancer (TNBC). We identified cross talk between histone acetylation and the glycolytic pathway resulting in a vulnerability of TNBC cell lines to inhibition of BRPF2/3 BRDs under conditions of glucose deprivation or GLUT1 inhibition. This chemical probe set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.

cell biology↗