Biology subjects

Rice, S.

Publications and source records attributed to Rice, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Cofilin Suppresses Tau-Induced Defects in Dense-Core Granule Formation and Aβ-Induced Neurodegeneration

Intracellular neurofibrillary tangles formed from hyperphosphorylated tau and extracellular amyloid plaques containing aggregated A{beta}-peptides, specific cleavage products of the Amyloid Precursor Protein (APP), are the primary histopathological hallmarks of Alzheimers Disease (AD), the leading cause of dementia in humans. However, the initiating steps that lead to these pathologies and early neurodegeneration, and the mechanisms by which tau- and A{beta}-induced effects might be linked remain unclear. Using the prostate-like secondary cell (SC) in Drosophila, we recently showed that A{beta} modulates normal APP- and membrane-associated protein aggregation in the dense-core granule (DCG) compartments of the regulated secretory pathway by interfering with subsequent membrane:DCG dissociation. This disrupts endolysosomal trafficking and propagates the resulting endolysosomal defects to other cells that endocytose the secreted abnormal DCG proteins. Here we show that overexpressing human tau also disrupts DCG aggregation and membrane:DCG dissociation inside SC secretory compartments, leading to increased endolysosomal targeting of these compartments. In a genetic screen, we find that knockdown of cofilin, which encodes an actin-severing protein required for dynamic remodelling of microfilaments, generates a similar phenotype. Consistent with this, overexpression of Cofilin, which is known to suppress tau-induced neurodegeneration in flies, reduces tau-induced DCG defects in SCs. Indeed, we find that Cofilin overexpression also suppresses A{beta}-induced degeneration in the fly eye. We conclude that membrane:DCG aggregate dissociation in DCG compartments is disrupted by both tau- and A{beta}-induced genetic changes that are relevant to AD, and this partially involves inhibition of actin cytoskeleton dynamics. Increasing actin remodelling activity can suppress neurodegeneration induced by both tau and A{beta}, suggesting that this process provides an important functional link between them that might be targeted therapeutically.

neuroscience↗

bioRxiv2026

Cutibacterium acnes-derived short-chain fatty acids drive lipogenesis and induce holocrine secretion in human sebocytes

Sebum lipids are one of the key ecological determinants of skin microbiome composition, where sebaceous sites are enriched with sebum utilising microbes such as Cutibacterium acnes. While sebaceous gland (SG) activation and sebogenesis are classically viewed as host-regulated processes, the association of C. acnes expansion with sebum production in the skin suggests a possible bidirectional host-microbe regulation. Using bacterial supernatants, we combined image-based lipid quantification, GC-FID metabolite profiling, lipid secretion quantification, and transcriptomic analysis to determine the metabolic drivers of the interaction between C. acnes and sebocytes. We found that C. acnes secretome significantly increased lipid droplet accumulation in sebocytes and propionate as the primary driver of this lipogenic response. Mechanistically, propionate reprogrammed the central carbon metabolism, redirecting carbon flux toward energy production and generation of precursors for lipid biosynthesis. Propionate also promoted lipid assembly pathways and modulated the composition of the secreted lipids from the treated sebocytes. We further show that propionate promotes expression of late sebocyte differentiation markers associated with holocrine secretion. Together, these findings redefine the relationship between microbiome and sebaceous glands, and identify C. canes as an active regulator promoting both sebogenesis and holocrine secretion for the release of lipids in the pilosebaceous unit.

molecular biology↗

bioRxiv2026

Rab11-exosome biogenesis regulators mediate Aβ-induced intercellular propagation of endolysosomal trafficking defects and neurodegeneration

Alzheimer's Disease (AD) is characterised by two histopathological hallmarks, intracellular tau-containing neurofibrillary tangles and extracellular amyloid plaques containing {beta}-amyloid (A{beta}), a specific cleavage product of Amyloid Precursor Protein (APP). Initiation of A{beta}-induced neuronal pathology, however, has been postulated to involve intracellular events affecting endolysosomal trafficking that can propagate between cells. Recent studies in non-neuronal Drosophila secondary cells (SCs) have revealed that A{beta} interferes with APP-regulated protein aggregation events, which package signalling molecules into insoluble dense-core granules (DCGs) during normal regulated secretion, inducing endolysosomal defects that are transferred to other cells. Here, using SCs, we show that knockdown of the gene encoding accessory ESCRT-III protein Chmp5, which selectively regulates the formation of intraluminal vesicles (ILVs) inside SC DCG compartments that are subsequently released as Rab11-exosomes, inhibits propagation of A{beta}-induced endolysosomal trafficking defects. Furthermore, knocking down Chmp5 or other accessory ESCRT-III genes also suppresses A{beta}-induced, neurodegeneration-dependent morphological defects in the Drosophila eye. We conclude that genes controlling the Rab11-exosome biogenesis pathway play a key role in both A{beta}-induced endolysosomal trafficking defects associated with aberrant regulated secretion and cellular events leading to neurodegeneration. Our findings indicate these processes are linked and may suggest new target pathways for future development of AD therapeutics.

neuroscience↗

bioRxiv2026

How a highly acidic SH3 domain binds to its intrinsically disordered partner through the formation of an encounter complex intermediate

Electrostatic interactions often play a role in determining the thermodynamic and kinetic properties of protein-protein interactions. However, the role of long-range electrostatic interactions in intrinsically disordered protein (IDP) binding is less clear, as they often bind in multiple steps including initial formation of a disordered encounter complex, followed by rearrangement into the bound state. We varied the salt concentration to probe the role of long-range electrostatic interactions in the binding of the highly charged AbpSH3 domain and the oppositely charged IDP ArkA. Using isothermal titration calorimetry, we observe that salt enthalpically destabilizes the bound complex. Molecular dynamics and NMR experiments reveal that salt has little effect on the bound state structure. However, simulations show that salt destabilizes the encounter complex intermediate, which primarily affects the association rate as measured by NMR. Consistent with these results, salt has the largest stabilizing effect on the apo SH3 domain, as cations substitute for the transient and long-range electrostatic interactions that can form with ArkA in the complex. We reveal a detailed picture of how a highly charged domain uses long-range, fuzzy, electrostatic interactions to help reach the bound state, a mechanism that is likely common among other highly charged domains that bind IDPs. TOC Image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/741257v1_ufig1.gif" ALT="Figure 1000"> View larger version (21K): org.highwire.dtl.DTLVardef@dfc7acorg.highwire.dtl.DTLVardef@1ae0438org.highwire.dtl.DTLVardef@19704adorg.highwire.dtl.DTLVardef@1b40b15_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2025

Incorporation of microbially salvaged urea-nitrogen into anabolic amino acids during hibernation in arctic ground squirrels

Hibernators rely on endogenous supplies of amino acids (AAs) and other nutrients to sustain organ function and skeletal muscle mass. Gut microbiota-mediated recycling of urea-nitrogen into AAs has long been considered a mechanism to assist in conserving nitrogen; however, the relevance of urea nitrogen salvage (UNS) to overall host physiology and metabolism is debated. We hypothesized that incorporation of microbially-liberated urea-nitrogen (MLUN) into AAs would be higher in host tissues of hibernating arctic ground squirrels compared to those of summer active squirrels, and that MLUN would support synthesis of anabolic AAs that regulate protein balance. To test this, we injected [13C, 15N2]-urea into summer squirrels and into squirrels hibernating at an ecologically relevant ambient temperature (-16{degrees}C). We found greater incorporation of MLUN into non-essential AAs and specific essential AAs in several tissues of hibernating squirrels compared to summer. We also observed increased 15N enrichment in leucine-isoleucine, citrulline and glutamine, anabolic AAs known to influence protein balance and trans-organ nitrogen balance. Compared to studies in which ground squirrels hibernated at ambient temperatures above 0{degrees}C, our results suggest that squirrels hibernating at subzero temperatures may up modulate synthesis of AAs that preserve protein and nitrogen balance during prolonged fasting and inactivity.

systems biology↗

bioRxiv2025

Bi-specific CAR-iNKT cell immunotherapy for high-risk KMT2A-rearranged leukemia outperforms CAR-T in an NKG2D-dependent manner and eradicates leptomeningeal disease

Current therapies, including autologous CAR-T immunotherapy, fail to cure half of infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2Ar-ALL). Here we deploy allogeneic iNKT cells, innately more powerful effectors than T cells, and equip them with CD19- and/or CD133-targeting CARs. Compared to mono-specific counterparts and bi-specific CAR-T, CD19-CD133 bi-specific CAR-iNKT have more potent anti-leukemia activity, they effectively target CAR antigen-low leukemia, eradicate medullary and leptomeningeal leukemia and induce sustained remissions without discernible hematologic toxicity. Mechanistically, dynamic CAR- and CAR antigen-dependent upregulation of the activating innate receptor NKG2D and its engagement by corresponding ligands on KMT2Ar-ALL cells lead to more potent anti-leukemia effect of CAR-iNKT over CAR-T cells, including against CAR antigen-negative leukemia. Thus, by engaging with two different types of leukemia-associated targets, CAR-iNKT provide a powerful platform for the treatment of KMT2Ar-ALL. This approach can be readily adapted for other high-risk malignancies, including those with otherwise difficult to target leptomeningeal involvement.

cancer biology↗

bioRxiv2024

A model, mixed-species urinary catheter biofilm derived from spinal cord injury patients

Complex multispecies biofilms consistently colonise the interior of indwelling urinary catheters, causing persistent asymptomatic bacteriuria and frequent symptomatic episodes in long-term catheterized individuals. Simple single-species models often fail to capture the complexities of mixed-species interactions, leading to limited conclusions about microbial behaviour and treatment efficacy. Additionally, using lab-based organisms can obscure the genomic diversity found in real-world infections. The primary objective of this study was to establish a stable and reproducible in vitro biofilm model derived from the multi-species clinical flora associated with catheter-related infections, reflecting the dynamics of in vivo infections. Biofilm samples from clinical catheters of spinal cord injury (SCI) participants were used to establish polymicrobial macro-fluidic models within catheters. Metagenomic techniques using short-read Illumina and long-read Oxford Nanopore sequencing was used to assess the community composition, produce metagenome-assembled genomes (MAGs), analyse strain-level phylogeny diversity and single nucleotide polymorphisms (SNP) of isolates. Antibiotic resistance tests using our models highlighted the drastic differences between planktonic bacteria, single-species, and multispecies biofilms. In silico analysis of antibiotic resistance further revealed a high number of varied resistance genes present in these communities. The models developed and characterised in this study are expected to facilitate more effective strategies to prevent and treat catheter-associated infections.

microbiology↗

bioRxiv2024

The fetal specific gene LIN28B is essential for human fetal B-lymphopoiesis and initiation of KMT2A::AFF1 infant leukemia

Infant ALL (iALL) is initiated in utero, most often by rearrangement of the KMT2A gene (KMT2Ar). It carries a very poor prognosis despite a lack of additional oncogenic driver mutations common in childhood ALL. Here, we aimed to identify specific properties of human fetal hematopoietic stem/progenitor cells (HSPC) that promote leukemic transformation in KMT2Ar iALL using molecular, functional and in vivo assays. First, by comparing transcriptomes of human fetal HSPC to adult HSPC we derived a fetal-specific gene signature and identified the fetal oncogene LIN28B and its downstream effectors among the top hits. These genes were also expressed in iALL. Functional assays revealed that LIN28B was essential in human fetal liver (FL) CD34+ cells to maintain proliferation and stemness, and support B- and NK-lymphopoiesis. To interrogate the role of LIN28B in iALL, we utilised a human FL-derived CRISPR-Cas9 KMT2A::AFF1 model. In this model, LIN28B-expressing leukemias were more proliferative in vitro and in vivo, with this advantage being lost upon LIN28B knockdown. Mechanistic studies showed that LIN28B acts by stabilizing key early B-lymphoid genes, epigenetic regulators, and cell cycle and anti-apoptotic genes. Finally, In the absence of LIN28B, human FL CD34+ cells fail to transform upon induction of KMT2A::AFF1 translocation. Thus, LIN28B has an essential role in normal human fetal B-lymphopoiesis, and is necessary for the initiation of KMT2A::AFF1 iALL in fetal cells in the absence of co-operating mutations. It has a role in making leukemias more aggressive, suggesting it is a potential target in LIN28B-expressing leukemias.

cancer biology↗

bioRxiv2023

Mechanism of action of Vitamin D (1,25-(OH)2-D3) on ovarian follicle growth: implications for women with Vitamin D deficiency and PCOS

Numerous observational and interventional studies have investigated the link between Vitamin D (VD) deficiency and reproductive outcomes, with contradictory results. VD is known to regulate steroidogenic enzymes crucial for human granulosa and cumulus cell function and genes that play a critical role in folliculogenesis have a vitamin D response element (VDRE) on their promoters. This study investigated whether deficient levels of 1,25-(OH)2-D3 altered ovarian cell function; and if the ovary could obtain bioactive 1,25-(OH)2-D3 via local enzymatic expression of CYP27B1, to counteract systemic deficiency. A variety of cells and tissues were used for the in vitro experiments as practicable. We have shown for the first time an increase in VDR expression in theca of larger compared to smaller follicles, which along with the ability of 1,25-(OH)2-D3 to decrease Anti-Mullerian hormone (AMH) expression, supports a role for 1,25-(OH)2-D3 in theca and granulosa cell function. Conversely, we have shown that very levels of 1,25-(OH)2-D3 equivalent to hypovitaminosis, inhibited thecal production of androstenedione and cAMP-driven E2 production. Human thecal and unluteinised GC are incredibly hard to obtain for research purposes, highlighting the uniqueness of our data set. For the first time we have demonstrated that deficient levels of 1,25-(OH)2-D3 also down-regulated insulin receptor expression, potentially reducing insulin sensitivity. We have shown that the ovary expresses CYP27B1 allowing it to make local bioactive 1,25-(OH)2-D3 which along with the upregulation in VDR expression in all ovarian cellular compartments, could be protective locally in counteracting systemic VD deficiency. To conclude a severely deficient VD environment (<2nM or <1ng/ml) could contribute to impaired ovarian cell function and hence potentially affect folliculogenesis/ovulation, but levels associated with mild deficiency may have less impact, apart from in the presence of hyperinsulinemia and insulin resistance.

physiology↗

bioRxiv2023

Direct visualization of bacterial multispecies infection and symbiotic interactions within human bladder epithelial cells

Urinary tract infections (UTI) are one of the most common bacterial infections worldwide. While the overall infection course is known on a macroscale, bacterial behavior is not fully understood at the cellular level and bacterial pathophysiology during multispecies infection is not well characterized. Here we establish co-infection models combined with high resolution imaging to compare single- and multi-species bladder cell invasion events in three common uropathogens: uropathogenic Escherichia coli (UPEC), Klebsiella pneumoniae and Enterococcus faecalis. While all three species invaded the bladder cells, under flow conditions the Gram-positive E. faecalis was significantly less invasive compared to the Gram-negative UPEC and K. pneumoniae. When introduced simultaneously during an infection experiment, all three bacterial species sometimes invaded the same bladder cell, at differing frequencies suggesting complex interactions between bacterial species and bladder cells. Inside host cells, we observed encasement of E. faecalis colonies specifically by UPEC. During subsequent dispersal from the host cells, only the Gram-negative bacteria underwent infection-related filamentation (IRF). Taken together, our data suggest that bacterial multispecies invasions of single bladder cells are frequent and support earlier studies showing intraspecies cooperation on a biochemical level during UTI.

microbiology↗

bioRxiv2022

PAF1 and FACT cooperate with MLL-AF4 to drive enhancer activity in leukemia

Aberrant enhancer activation has been identified as a key mechanism driving oncogene expression in many cancers. Here we use TOPmentation (Transcription factor-OPtimized ChIPmentation) to probe enhancer usage in primary MLL-rearranged acute lymphoblastic leukemia. We find that MLL-AF4, commonly held to promote transcription by binding to gene promoters, is also present at many active enhancers, where it assembles a complex of transcriptional co-activators normally found in the gene body. This includes DOT1L, ENL, PAF1, and a newly identified interaction with the histone chaperone FACT. By chemical degradation, we demonstrate that PAF1 and FACT are required for enhancer activity, including maintaining histone H3K27 acetylation, enhancer RNA transcription and enhancer-promoter interactions. This work identifies novel roles for PAF1 and FACT in enhancer function, and reveals an enhancer-targeting mechanism by which MLL-AF4 upregulates transcription, recruiting transcription machinery through a network of multivalent interactions to control enhancer activity and gene expression in acute leukemias.

molecular biology↗

bioRxiv2021

Differential regulation of mouse hippocampal gene expression sex differences by chromosomal content and gonadal sex

Common neurological disorders, like Alzheimers disease (AD), multiple sclerosis (MS), and autism, display profound sex differences in prevalence and clinical presentation. However, sex differences in the brain with health and disease are often overlooked in experimental models. Sex effects originate, either directly or indirectly, from hormonal or sex chromosomal mechanisms. To delineate the contributions of genetic sex (XX v. XY) versus gonadal sex (ovaries v. testes) to the epigenomic regulation of hippocampal sex differences, we use the Four Core Genotypes (FCG) mouse model to uncouple chromosomal and gonadal sex. Transcriptomic and epigenomic analyses of [~]12-month-old FCG mice hippocampi, revealed genomic context-specific regulatory effects of genotypic and gonadal sex on X- and autosome-encoded gene expression and DNA modification patterns. X-chromosomal epigenomic patterns, classically associated with X-inactivation, were established almost entirely by genotypic sex, independent of gonadal sex. Differences in X-chromosome methylation were primarily localized to gene regulatory regions including promoters, CpG islands, CTCF binding sites, and active/poised chromatin, with an inverse relationship between methylation and gene expression. Whereas, autosomal gene expression demonstrated regulation by both genotypic and gonadal sex, particularly in immune processes. These data demonstrate an important regulatory role of sex chromosomes, independent of gonadal sex, on sex-biased hippocampal transcriptomic and epigenomic profiles. Future studies will need to further interrogate specific CNS cell types, identify the mechanisms by which sex chromosomes regulate autosomes, and differentiate organizational from activational hormonal effects.

genomics↗

bioRxiv2020

A novel human fetal liver-derived model reveals that MLL-AF4 drives a distinct fetal gene expression program in infant ALL

Although 90% of children with acute lymphoblastic leukemia (ALL) are now cured1, the prognosis of infant-ALL (diagnosis within the first year of life) remains dismal2. Infant-ALL is usually caused by a single genetic hit that arises in utero: rearrangement of the MLL/KMT2A gene (MLL-r). This is sufficient to give rise to a uniquely aggressive and treatment-refractory leukemia compared to older children with the same MLL-r3-5. The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. This paper addresses the hypothesis that fetal-specific gene expression programs co-operate with MLL-AF4 to initiate and maintain infant-ALL. Using direct comparison of fetal and adult HSC and progenitor transcriptomes we identify fetal-specific gene expression programs in primary human cells. We show that MLL-AF4-driven infant-ALL, but not MLL-AF4 childhood-ALL, displays expression of fetal-specific genes. In a direct test of this observation, we find that CRISPR-Cas9 gene editing of primary human fetal liver cells to produce a t(4;11)/MLL-AF4 translocation replicates the clinical features of infant-ALL and drives infant-ALL-specific and fetal-specific gene expression programs. These data strongly support the hypothesis that fetal-specific gene expression programs co-operate with MLL-AF4 to initiate and maintain the distinct biology of infant-ALL.

cancer biology↗

bioRxiv2020

Phenotypic analysis of an MLL-AF4 gene regulatory network reveals indirect CASP9 repression as a mode of inducing apoptosis resistance.

Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than studying single TF binding events in isolation. Chromosomal translocations of the Mixed Lineage Leukemia gene (MLL) produce MLL fusion proteins such as MLL-AF4, causing poor prognosis acute lymphoblastic leukemias (ALLs). MLL-AF4 is thought to drive leukemogenesis by directly binding to genes and inducing aberrant overexpression of key gene targets, including anti-apoptotic factors such as BCL-2. However, this model minimizes the potential for circuit generated regulatory outputs, including gene repression. To better understand the MLL-AF4 driven regulatory landscape, we integrated ChIP-seq, patient RNA-seq and CRISPR essentiality screens to generate a model GRN. This GRN identified several key transcription factors, including RUNX1, that regulate target genes using feed-forward loop and cascade motifs. We used CRISPR screening in the presence of the BCL-2 inhibitor venetoclax to identify functional impacts on apoptosis. This identified an MLL-AF4:RUNX1 cascade that represses CASP9, perturbation of which disrupts venetoclax induced apoptosis. This illustrates how our GRN can be used to better understand potential mechanisms of drug resistance acquisition. Graphical abstract caption O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/179796v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@cca8f2org.highwire.dtl.DTLVardef@67b289org.highwire.dtl.DTLVardef@1fa44aeorg.highwire.dtl.DTLVardef@1b32487_HPS_FORMAT_FIGEXP M_FIG A network model of the MLL-AF4 regulatory landscape identifies feed-forward loop and cascade motifs. Functional screening using CRISPR and venetoclax identified an MLL-AF4:RUNX1:CASP9 repressive cascade that impairs drug-induced cell death. C_FIG

genomics↗

bioRxiv2020

Analyzing Genomic Data Using Tensor-Based Orthogonal Polynomials

An important goal in molecular biology is to quantify both the patterns across a genomic sequence and the relationship between phenotype and underlying sequence. We propose a multivariate tensor-based orthogonal polynomial approach to characterize nucleotides or amino acids in a given sequence and map corresponding phenotypes onto the sequence space. We have applied this method to a previously published case of small transcription activating RNAs (STARs). Covariance patterns along the sequence showcased strong correlations between nucleotides at the ends of the sequence. However, when the phenotype is projected onto the sequence space, this pattern doesnt emerge. When doing second order analysis and quantifying the functional relationship between the phenotype and pairs of sites along the sequence, we identified sites with high regressions spread across the sequence, indicating potential intramolecular binding. In addition to quantifying interactions between different parts of a sequence, the method quantifies sequence-phenotype interactions at first and higher order levels. We discuss the strengths and constraints of the method and compare it to computational methods such as machine learning approaches. An accompanying command line tool to compute these polynomials is provided. We show proof of concept of this approach and demonstrate its potential application to other biological systems.

bioinformatics↗

bioRxiv2019

Evolution with complex selection and transmission

Inheritance is the key factor making biological evolution possible. Despite this central role, transmission is often bundled into the simplifying assumptions of evolutionary models, making it difficult to see how changes in the patterns of transmission influence evolutionary dynamics. We present a mathematical formalism for studying phenotypic evolution, under any selection regime and with any transmission rules, that clearly delineates the roles played by transmission, selection, and interactions between the two.\n\nTo illustrate the approach, we derive models in which heritability and and fitness are influenced by the same environmental factors - producing a covariation between selection and transmission. By itself, variation in heritability does not influence directional evolution. However, we show that any covariation between heritability and selection can have a sub-stantial effect on trait evolution. Moderate differences in heritability between environments can lead to organisms adapting much more to environments with higher heritability, and can pull a population off of an \"adaptive peak\". When habitat preference is allowed to evolve as well, variation in heritability between environments can lead to organisms exclusively using the environment in which heritability is highest. This effect is most pronounced when initial habitat selection is weak.

evolutionary biology↗

bioRxiv2019

Interspecies interactions in a model, mixed-species biofilm are determined by physiological traits and environmental factors

Interspecies interactions in bacterial biofilms have important impacts on the composition and function of communities in natural and engineered systems. To investigate these interactions, synthetic communities provide experimentally tractable systems. Agar-surface colonies are similar to biofilms and have been used for investigating the eco-evolutionary and biophysical forces that determine community composition and spatial distribution of bacteria. Prior work has focused on intraspecies interactions, using differently fluorescent tagged but identical or genetically modified strains of the same species. Here, we investigated how physiological differences determine the community composition and spatial distribution in synthetic communities of Pseudomonas aeruginosa, Pseudomonas protegens and Klebsiella pneumoniae. Using quantitative microscopic imaging, we found that interspecies interactions in multispecies colonies are influenced by type IV pilus mediated motility, extracellular matrix secretion, environmental parameters and the specific species involved. These results indicate that the patterns observable in mixed species colonies can be used to understand the mechanisms that drive interspecies interactions, which are dependent on the interplay between specific species physiology and environmental conditions.

microbiology↗

bioRxiv2018

Functional Testing of Thousands of Osteoarthritis-Associated Variants for Regulatory Activity

To date, genome-wide association studies have implicated at least 35 loci in osteoarthritis, but due to linkage disequilibrium, we have yet to pinpoint the specific variants that underlie these associations, nor the mechanisms by which they contribute to disease risk. Here we functionally tested 1,605 single nucleotide variants associated with osteoarthritis for regulatory activity using a massively parallel reporter assay. We identified six single nucleotide polymorphisms (SNPs) with differential regulatory activity between the major and minor alleles. We show that our most significant hit, rs4730222, drives increased expression of an alternative isoform of HBP1 in a heterozygote chondrosarcoma cell line, a CRISPR-edited osteosarcoma cell line, and in chondrocytes derived from osteoarthritis patients.

genomics↗