Biology subjects

Chandler, D.

Publications and source records attributed to Chandler, D..

7 recordsLinked to original sources

bioRxiv2025

Tracking the zombie ant graveyards' dynamics at Mulu National Park, Borneo, Malaysia

Ophiocordyceps unilateralis sensu lato is a parasitoid fungus that predominantly infects ants from the Camponotini tribe, inducing behavioural changes to enhance its survival and reproduction. The most notable change occurs during the final infection phase, where the infected ant leaves its nest to perform the death grip, hanging upside down and biting onto a substrate to anchor itself. In the tropics, these infected ants congregate at specific locations known as zombie graveyards, which have optimal conditions for spore dispersal. This study examines the spatial dynamics of known graveyards at a national park in Borneo, Malaysia, by assessing existing sites and identifying new ones. We located old graveyards at Night Walk and Paku Trail and discovered a new one at Botany Loop. The density of ant cadavers per quadrat increased slightly, from 1-3 ants/m2 to 2-4 ants/m2. While the graveyard size at Night Walk remained similar, Paku Trail experienced a nearly two-fold reduction, decreasing from 197 m2 to 97 m2. At Night Walk, three ant hosts were identified, with Colobopsis leonardi being the dominant ant host across all graveyards. Without genetic tests, we could not confirm whether the same O. unilateralis infects all ants in the graveyards. Our findings suggest a general site fidelity of zombie graveyards, with hotspot densities varying spatially, potentially influenced by microclimatic changes. Long-term monitoring of graveyard dynamics is essential for understanding natural infections and the effects of environmental conditions on parasitoid-host ecology.

ecology↗

bioRxiv2024

SATB2 and circ3915 RNA chromatin dysregulation drive KRAS-like oncogenic transformation

Even though epigenetic factors contribute to oncogenesis, most human cancer models still assume that disease originates from driver DNA mutations. Thus, it is still unclear if non-genetic mechanisms are sufficient to trigger malignant transformation. Special AT-rich binding protein 2 (SATB2) is a chromatin organizer that brings distal DNA elements into close proximity, thus remodeling chromatin structures to reprogram cell-specific and/or developmentally-sensitive gene networks. Here, we discover that SATB2 generates a co-expressed circ3915 RNA that is translated into a peptide and co-locates with SATB2 in the cell nucleus. Ectopic SATB2 or circ3915 over- expression rearranges global chromatin accessibility, generates KRAS- and NFE2L2-like oncogenic gene expression patterns, and transforms lung epithelial cells independent of driver mutations. Thus, oncogenic pathways can be activated in mammalian cells without pre-disposing mutations in oncogenes or epigenetic regulators. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/616681v1_ufig1.gif" ALT="Figure 1000"> View larger version (32K): org.highwire.dtl.DTLVardef@1314b69org.highwire.dtl.DTLVardef@14df9e1org.highwire.dtl.DTLVardef@505bddorg.highwire.dtl.DTLVardef@1bf3fab_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Blockade of Interleukin-6 (IL-6) Signaling in Dedifferentiated Liposarcoma (DDLPS) Decreases Mouse Double Minute 2 (MDM2) Oncogenicity via Alternative Splicing

Effective therapies for retroperitoneal (RP) dedifferentiated liposarcoma (DDLPS) remain unavailable. Loco-regional recurrence occurs in >80% of cases; 5-year disease-specific survival is only 20%. DDLPS is especially prevalent in the retroperitoneum and abdomen; evaluation of the DDLPS microenvironment in these high-fat compartments appears pertinent. Adipose is a main supplier of interleukin-6 (IL6); excessive activation of IL6 signal transducer glycoprotein 130 (GP130) underlies the development of some diseases. The role of GP130 pathway activation remains unstudied in DDLPS, so we examined the role of microenvironment fat cell activation of the IL6/GP130 signaling cascade in DDLPS. All DDLPS tumors and cell lines studied expressed elevated levels of the GP130-encoding gene IL6ST and GP130 protein compared to normal tissue and cell line controls. IL6 increased DDLPS cell growth and migration, possibly through increased signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) activation, and upregulated mouse double minute 2 (MDM2). GP130 loss conveyed opposite effects; pharmacological blockade of GP130 by SC144 produced the MDM2 splice variant MDM2-ALT1, known to inhibit full length MDM2 (MDM2-FL). Although genomic MDM2 amplification is pathognomonic for DDLPS, mechanisms driving MDM2 expression, regulation, and function beyond the MDM2:p53 negative feedback loop are poorly understood. Our findings suggest a novel preadipocyte DDLPS-promoting role due to IL6 release, via upregulation of DDLPS MDM2 expression. Pharmacological GP130 blockade reduced the IL6-induced increase in DDLPS MDM2 mRNA and protein levels, possibly through enhanced expression of MDM2-ALT1, a possibly targetable pathway with potential as future DDLPS patient therapy.

molecular biology↗

bioRxiv2023

Manipulating multi-level selection in a fungal entomopathogen reveals social conflicts and a method for improving biocontrol traits

Changes in parasite virulence are commonly expected to lead to trade-offs in other life history traits that can affect fitness. Understanding these trade-offs is particularly important if we want to manipulate the virulence of microbial biological control agents. Theoretically, selection across different spatial scales, i.e. between- and within-hosts, shapes these trade- offs. However, trade-offs are also dependent on parasite biology. Despite their applied importance the evolution of virulence in fungal parasites is poorly understood: virulence can be unstable in culture and commonly fails to increase in simple passage experiments. We hypothesized that manipulating selection intensity at different scales would reveal virulence trade-offs in a fungal pathogen of aphids, Akanthomyces muscarius. Starting with a genetically diverse stock we selected for infectivity, parasite yield or speed of kill by manipulating competition within and between hosts and between groups of hosts over 7 rounds of infection. We characterized ancestral and evolved lineages by whole genome sequencing and by measuring virulence, growth rate, sporulation and fitness. While several lineages showed increases in virulence, we saw none of the trade-offs commonly found in obligately-killing parasites. Phenotypically similar lineages within treatments often shared multiple single-nucleotide variants, indicating strong convergent evolution. The most dramatic phenotypic changes were in timing of sporulation and spore production in vitro. We found that early sporulation led to reduced competitive fitness but could increase yield of spores on media, a trade-off characteristic of social conflict. Notably, the selection regime with strongest between-group competition and lowest genetic diversity produced the most consistent shift to early sporulation, as predicted by social evolution theory. Mutli-level selection therefore revealed social interactions novel to fungi and showed that these biocontrol agents have the genomic flexibility to improve multiple traits -virulence and spore production - that are often in conflict in other parasites. Author summaryUnderstanding the ecological forces that shape virulence is a key challenge in evolutionary biology. Here we investigated how competition at different levels of selection (within-hosts, between-hosts, between populations) could alter investment in virulence in a fungal entomopathogen. We predicted that cooperative investment in virulence would increase at higher scales of competition and aimed to further our understanding of potential trade-offs shaping life-history of a fungal insect pathogens. We found moderate increases in virulence in different selection regimes but importantly, none of the commonly expected trade-offs, such as that between spore production and virulence or a relationship between virulence and growth rate, which is consistent with cooperation. However, we found convergent genetic changes and significant differences in timing and production of spores, dependent how we manipulated scales of selection. Our data suggests that this is driven by social conflict regarding the timing of sporulation. This carries fundamental importance for understanding how varying selection pressure at different scales shape pathogen life history. In addition, these results also have applied importance for understanding how to improve and select for beneficial traits in biocontrol agents.

evolutionary biology↗

bioRxiv2023

Developmental priming of cancer susceptibility

DNA mutations are necessary drivers of cancer, yet only a small subset of mutated cells go on to cause the disease. To date, the mechanisms that determine which rare subset of cells transform and initiate tumorigenesis remain unclear. Here, we take advantage of a unique model of intrinsic developmental heterogeneity (Trim28+/D9) and demonstrate that stochastic early life epigenetic variation can trigger distinct cancer-susceptibility states in adulthood. We show that these developmentally primed states are characterized by differential methylation patterns at typically silenced heterochromatin, and that these epigenetic signatures are detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis. These results provide proof-of-concept that intrinsic developmental heterogeneity can prime individual, life-long cancer risk.

cancer biology↗

bioRxiv2022

Alternatively Spliced Landscape of PPARγ mRNA in Podocytes is Distinct from Adipose Tissue

Podocytes are highly differentiated epithelial cells, and their structural and functional integrity is compromised in a majority of glomerular and renal diseases, leading to proteinuria, chronic kidney disease, and kidney failure. Traditional agonists (e.g., pioglitazone) and selective modulators (e.g., GQ-16) of peroxisome-proliferator-activated-receptor-{gamma} (PPAR{gamma}) reduce proteinuria in animal models of glomerular disease and protect podocytes from injury via PPAR{gamma} activation. This indicates a pivotal role for PPAR{gamma} in maintaining glomerular function through preservation of podocytes distinct from its well-understood role in driving insulin sensitivity and adipogenesis. While its transcriptional role in activating adipokines and adipogenic genes is well-established in adipose tissue, liver and muscle, understanding of podocyte PPAR{gamma} signaling remains limited. We performed a comprehensive analysis of PPAR{gamma} mRNA variants due to alternative splicing, in human podocytes and compared with adipose tissue. We found that podocytes express the ubiquitous PPAR{gamma} Var 1 (encoding {gamma}1) and not Var2 (encoding {gamma}2), which is mostly restricted to adipose tissue and liver. Additionally, we detected expression at very low level of Var4, and barely detectable levels of other variants, Var3, Var11, VartORF4 and Var9, in podocytes. Furthermore, a distinct podocyte vs adipocyte PPAR-promoter-response-element containing gene expression, enrichment and pathway signature was observed, suggesting differential regulation by podocyte specific PPAR{gamma}1 variant, distinct from the adipocyte-specific {gamma}2 variant. In summary, podocytes and glomeruli express several PPAR{gamma} variants, including Var1 ({gamma}1) and excluding adipocyte-specific Var2 ({gamma}2), which may have implications in podocyte specific signaling and pathophysiology. This suggests that new selective PPAR{gamma} modulators can be potentially developed that will be able to distinguish between the two forms, {gamma}1 and {gamma}2, thus forming a basis of novel targeted therapeutic avenues.

molecular biology↗

bioRxiv2020

Splice-switching of the insulin receptor in rhabdomyosarcoma: Rescuing the IR-B isoform for better treatment options.

Rhabdomyosarcoma (RMS) is an aggressive pediatric tumor with poor prognosis for metastasis and recurrent disease. Large scale sequencing endeavors demonstrate that RMS tumors have limited mutations and a dearth of driver mutations that are precisely targetable. However, IGF2 signaling is known to be grossly altered in RMS. The IGF2 signalling molecule binds both its innate IGF1 receptor as well as the insulin-receptor-variant-A (IR-A) with high affinity. Mitogenic and proliferative signalling via the canonical IGF2 pathway is therefore augmented by IR-A. The insulin receptor (IR) which is a transmembrane tyrosine-kinase receptor exists in two alternatively spliced isoforms, IR-A and IR-B. In this study, we show that RMS patients express increased IR-A compared to control tissues that express predominantly the IR-B isoform. We also found that Hif1a is significantly increased in RMS tumors, portraying their hypoxic phenotype. Furthermore, the alternative-splicing of IR adapts to produce more IR-A in response to hypoxic stress. Upon examining the pre-mRNA structure of the gene, we identified a hypoxia-responsive-element, which is also the binding site for the RNA-binding protein CUG-BP1. We designed Splice-Switching-Oligonucleotides (SSO) against this binding site to decrease the levels of IR-A in RMS cell-lines and consequently rescue the IR-B expression levels. SSO treatment resulted in significant reductions in proliferation, migration and angiogenesis. Our data show promising insight into how impeding the IGF-2 pathway by reducing IR-A expression mitigates tumor growth. Our data reveal that RMS tumors use IR alternative-splicing as yet another survival strategy which can be exploited as therapeutic intervention in conjunction with already established anti-IGF-1 receptor therapies.

cancer biology↗