Biology subjects

Chang, S.-M.

Publications and source records attributed to Chang, S.-M..

6 recordsLinked to original sources

bioRxiv2026

COPAL: An ensemble of protein-ligand co-folding models enriches preferred ligand predictions for the LuxR-family of quorum sensing receptors

Acyl-homoserine lactone (AHL) quorum sensing enables many species of proteobacteria to coordinate collective behaviors. In such systems, a synthase produces an AHL signal, which is sensed by a LuxR-family receptor. Despite extensive genomic annotation of LuxR homologs, preferred AHLs for most receptors remain unknown, limiting functional understanding of quorum sensing across diverse bacteria. Here, we present the COPAL (combining ordered predictions of audited ligands) pipeline, which integrates multiple protein-ligand co-folding models to identify preferred AHLs for a specific LuxR. Benchmarking on a leakage-controlled subset of 96 experimentally characterized LuxR-AHL pairs shows that COPAL places the preferred AHL within the top-6 candidates (out of 58) for 68% of receptors, outperforming every individual co-folding model. Further, inter-model agreement correlates with ranking accuracy, offering an indication of confidence. We show that COPAL resolves the specificity shift induced by three-point mutations in LasR and correctly nominates C8-HSL as the preferred ligand for the previously uncharacterized Mesorhizobium sp. NJ3 receptor, which we verified experimentally. Finally, we release the Ranked AHL-LuxR Prediction Hub (RALPH), comprising precomputed rankings for about 10,000 unique LuxR homologs. More broadly, COPAL shows that unweighted rank aggregation of complementary co-folding models offers a general strategy for predicting receptor-ligand specificity in data-scarce biological systems.

biochemistry↗

bioRxiv2024

The protease interpain A of Prevotella intermedia promotes human OSCC cells proliferation and migration

Prevotella intermedia has been increasingly recognized as a potential contributor to oral squamous cell carcinoma (OSCC), yet the underlying mechanisms remain poorly defined. In this study, we identified interpain A (InpA), a cysteine protease secreted by P. intermedia, as a key virulence factor that promotes oral epithelial cell proliferation and OSCC cell migration. Conditioned medium (CM) derived from P. intermedia strain ATCC 25611 enhanced proliferation in both normal oral keratinocytes (SG cells) and OSCC cell lines (SCC-15, SAS). The pro-proliferative effect was abolished upon heat inactivation of the CM and inhibited by E64, a cysteine protease inhibitor, and FSLLRY-NH2, a PAR-2 antagonist, suggesting the involvement of protease-activated receptor-2 (PAR-2) signaling. InpA was highly secreted by strain ATCC 25611 but not by clinical isolates lacking proliferative effects, and RT-qPCR confirmed higher inpA expression in OSCC-derived strains compared to non-cancer controls. Recombinant InpA (rInpA) mimicked the effect of CM, inducing proliferation and migration, which were blocked by PAR-2 inhibition. Transcriptomic and protein-level screening in SG cells revealed activation of EGFR and downstream RAS-RAF-MEK-ERK signaling. Furthermore, in a colorectal cancer (CRC) mouse model, oral administration of P. intermedia led to increased tumor formation, suggesting a broader oncogenic potential. These findings highlight InpA as a PAR-2-activating protease that may contribute to OSCC and potentially other cancers associated with oral microbiota dysbiosis.

cancer biology↗

bioRxiv2022

Not just flowering time: A resurrection approach shows floral attraction traits are changing over time

Contemporary anthropogenic changes in climate and landscape form a complex set of selective pressures acting on natural systems, yet, in many systems, we lack information about both whether and how organisms may adapt to these changes. In plants, research has focused on climate-induced changes in phenology and the resultant potential for disruption of plant-pollinator interactions, however there remains a paucity of knowledge regarding how other pollinator-mediated traits may be involved in adaptive response. Here, we use resurrection experiments to investigate the phenotypic basis of adaptation in a mixed-mating system plant, the common morning glory (Ipomoea purpurea). Specifically, we measure temporal and spatial changes in traits grouped into three categories relevant to plant-pollinator interactions - floral morphology, floral rewards, and floral phenology. We show a significant temporal increase in corolla size and shift to earlier flowering times, as well as a potential for increased investment in floral rewards, all of which are driven primarily by populations at more northern latitudes. Additionally, we find evidence for directional selection on floral morphology and phenology, and evidence of balancing selection acting on anther-stigma distance. Overall, these results show an adaptive response in line with greater investment in pollinator attraction rather than self-pollination and fine-scale spatial differences in adaptive potential.

evolutionary biology↗

bioRxiv2019

Parallel and nonparallel genomic responses contribute to herbicide resistance in Ipomoea purpurea, a common agricultural weed

The repeated evolution of herbicide resistance has been cited as an example of genetic parallelism, wherein separate species or genetic lineages utilize the same genetic solution in response to selection. However, most studies that investigate the genetic basis of herbicide resistance examine the potential for changes in the protein targeted by the herbicide rather than considering genome-wide changes. We used a population genomics screen and targeted exome re-sequencing to uncover the potential genetic basis of glyphosate resistance in the common morning glory, Ipomoea purpurea, and to determine if genetic parallelism underlies the repeated evolution of resistance across replicate resistant populations. We found no evidence for changes in 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), glyphosates target protein, that were associated with resistance, and instead identified five genomic regions that show evidence of selection. Within these regions, genes involved in herbicide detoxification--cytochrome P450s, ABC transporters, and glycosyltransferases--are enriched and exhibit signs of selective sweeps. One region under selection shows parallel changes across all assayed resistant populations whereas other regions exhibit signs of divergence. Thus, while it appears likely that the physiological mechanism of resistance in this species is likely the same among resistant populations, we find patterns of both similar and divergent selection across separate resistant populations at particular loci.

evolutionary biology↗

bioRxiv2018

Identifying individual risk rare variants using protein structure-guided local tests (POINT)

Rare variants are of increasing interest to genetic association studies because of their etiological contributions to human complex diseases. Due to the rarity of the mutant events, rare variants are routinely analyzed on an aggregate level. While aggregation analyses improve the detection of global-level signal, they are not able to pinpoint causal variants within a variant set. To perform inference on a localized level, additional information, e.g., biological annotation, is often needed to boost the information content of a rare variant. Following the observation that important variants are likely to cluster together on functional domains, we propose a protein structure guided local test (POINT) to provide variant-specific association information using structure-guided aggregation of signal. Constructed under a kernel machine framework, POINT performs local association testing by borrowing information from neighboring variants in the 3-dimensional protein space in a data-adaptive fashion. Besides merely providing a list of promising variants, POINT assigns each variant a p-value to permit variant ranking and prioritization. We assess the selection performance of POINT using simulations and illustrate how it can be used to prioritize individual rare variants in PCSK9 associated with low-density lipoprotein in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data.\n\nAuthor summaryWhile it is known that rare variants play an important role in understanding associations between genotype and complex diseases, pinpointing individual rare variants likely to be responsible for association is still a daunting task. Due to their low frequency in the population and reduced signal, localizing causal rare variants often requires additional information, such as type of DNA change or location of variant along the sequence, to be incorporated in a biologically meaningful fashion that does not overpower the genotype data. In this paper, we use the observation that important variants tend to cluster together on functional domains to propose a new approach for prioritizing rare variants: the protein structure guided local test (POINT). POINT uses a genes 3-dimensional protein folding structure to guide aggregation of information from neighboring variants in the protein in a robust manner. We show how POINT improves selection performance over single variant tests and sliding window approaches. We further illustrate how it can be used to prioritize individual rare variants using the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data, finding five promising variants within PCSK9 in association with low-density lipoprotein, including three new mutations near the PCSK9-LDLR binding domain.

bioinformatics↗

bioRxiv2017

Environmental Influences On The Mating System Of The Common Morning Glory

The balance between selfing and outcrossing is a life history trait of major concern with deep evolutionary consequences in mixed mating species. Yet, our current understanding of the proximate and ultimate determinants of species mating system is still unsatisfactory and largely theoretical. Indeed, evolutionary biologists are still puzzled by the often dramatic variation of mating strategies within single species. Of particular concern is the extent to which environmental conditions shape patterns of variation and covariation of mating system components within species. Here, we address this concern in the common morning glory (Ipomoea purpurea) by taking advantage of an extensive dataset of floral traits, genetic estimates of selfing and inbreeding, and relevant environmental factors compiled for 22 populations of this species distributed along a disparate set of environments along Southeast and Midwest USA. Combining a powerful array of parametric and model-free statistical approaches, we robustly identify a set of natural and anthropogenic environmental factors underlying population-level variation in selfing, inbreeding, and flower morphology. Remarkably, individual mating system components are found to be associated with different environmental factors and only loosely associated with each other, and thus potentially under multiple different selective pressures. These results not only corroborate theoretical expectations of the significant role the environment plays in the local determination of mating systems, but also provide compelling evidence of complex underlying interactions between multiple evolutionary processes.

plant biology↗