Biology subjects

Lau, G.

Publications and source records attributed to Lau, G..

7 recordsLinked to original sources

bioRxiv2026

Transcriptome-wide Differential Expression and Splicing in Inflammatory Bowel Disease Patients

The inflammatory bowel diseases (IBD), comprising mainly Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic intestinal inflammation driven in part by complex genetic and gene regulatory mechanisms. Although transcriptomic studies have defined broad expression changes in IBD, the contribution of alternative splicing to disease-associated molecular variation remains less clear. We therefore integrated differential expression (DE) and differential splicing (DS) analyses in macroscopically uninvolved colonic mucosal biopsies from patients with either CD or UC along with non-IBD controls to define gene expression and intron-usage changes across disease subtypes. We identified 491 DS and 316 DE genes in CD vs. non-IBD, and 1,298 DS and 1,107 DE genes in UC vs. non-IBD. DS and DE genes were nearly mutually exclusive, with no overlapping genes in CD and 16 in UC. Consistent with this result, pathway analysis showed that differentially expressed and differentially spliced genes were associated with related but distinct biological programs. DE genes were involved in chromatin organization, transcriptional regulation, and metabolic pathways for glycans and drugs, whereas DS genes were enriched for splicing, cellular signaling, and lipid metabolism. We found substantial similarity in enriched pathways across CD and UC with some notable exceptions, including increased enrichment of DS and DE genes involved in extracellular vesicles and exosomes in CD and enrichment of DS genes in ER-to-Golgi trafficking and stress granules in UC. Direct comparisons of CD and UC patients additionally show differential splicing usage in genes involved in cell adhesion pathways. These findings identify alternative splicing as a major contributor to transcriptomic changes in IBD that is largely distinct from changes in expression level and provide a broader view of molecular contributors to IBD.

genomics↗

bioRxiv2026

Bacteroides intestinalis-Driven Arabinoxylan Fermentation Mitigates Inflammatory and Metabolic Dysfunction

Insufficient dietary fiber intake is closely linked to gut microbiome dysfunction and increased risk of noncommunicable diseases. Synergistic synbiotics, pairing defined microbes with their dietary substrates, offer a precise strategy to restore microbiome function. Here, we show that pairing the human colonic commensal Bacteroides intestinalis with insoluble wheat arabinoxylan (inWAX) yields pronounced metabolic and anti-inflammatory benefits. Using mono-associated gnotobiotic mice and high-fat diet-induced obese mice, we demonstrate that this synbiotic enhances resistance to intestinal inflammation and improves glucose homeostasis. Mechanistically, this synbiotic increases production of 6-hydroxylated bile acids with anti-diabetic and anti-steatotic effects. It also promotes microbial transformation of phenolic compounds and redirects protein metabolism toward neuroactive metabolites. These metabolic shifts are accompanied by transcriptional remodeling in the colon, spleen and liver, involving induction of genes essential for circadian rhythm, lipid metabolism, immune defense, and bile acid 6-hydroxylation. Notably, Y chromosome-linked genes associated with epigenetic regulation and protein turnover are also induced, suggesting a potential sex-specific response to synbiotics. Together, our findings establish a mechanistic framework for targeted synbiotic interventions to combat inflammatory and metabolic disorders.

microbiology↗

bioRxiv2025

Reference-guided Genome Assembly of Long Non-coding RNA Transcripts reveals Target Genes Associated With Crohn's Disease

Crohns disease (CD) is highly heterogeneous in presentation and progression with no cure. Molecular phenotyping has been used to elucidate cellular and tissue-based alterations to characterize drivers and effects of disease. One currently understudied class of functional molecules is long non-coding RNAs (lncRNAs). Studying the full lncRNA landscape in IBD is challenging due in part to an incomplete lncRNA annotation and a lack of their functional characterization in tissues of interest. We used a genome-guided alignment strategy to assemble predicted lncRNA transcripts using short RNA-sequencing data from colon tissue of adult patient samples. When combining our predicted lncRNAs with previous lncRNA annotations, we determined 98 that were differentially expressed, recapitulating many from previous IBD studies while also uncovering new ones. We built gene co-expression networks to cluster lncRNAs with functionally characterized protein-coding genes. Clusters containing differential lncRNAs were correlated to disease status and associated with pathways related to the humoral immune response, metabolism, and tissue regeneration. We uncovered multiple differential lncRNAs whose expression significantly correlated with nearby differential protein-coding genes that have also been differentially expressed in other IBD datasets, such as PITX2. We focused on a predicted lncRNA that is antisense to the PITX2-adjacent lncRNA PANCR, which we called PANCR-AS1, and provide multiple lines of evidence that support PANCR-AS1 functioning as an enhancer of PITX2 expression. Overall, we determined lncRNAs that are potential contributors to CD pathogenesis. We developed a robust pipeline for identifying lncRNAs in diseased and non-diseased tissue that are absent from reference annotations. We also outlined a framework to pinpoint significant disease-associated lncRNAs with potential functional activity related to their nearby protein-coding genes.

genomics↗

bioRxiv2024

eQTL in diseased colon tissue identifies novel target genes associated with IBD

Genome-wide association studies (GWAS) have identified over 300 loci associated with the inflammatory bowel diseases (IBD), but putative causal genes for most are unknown. We conducted the largest disease-focused expression quantitative trait loci (eQTL) analysis using colon tissue from 252 IBD patients to determine genetic effects on gene expression and potential contribution to IBD. Combined with two non-IBD colon eQTL studies, we identified 194 potential target genes for 108 GWAS loci. eQTL in IBD tissue were enriched for IBD GWAS loci colocalizations, provided novel evidence for IBD-associated genes such as ABO and TNFRSF14, and identified additional target genes compared to non-IBD tissue eQTL. IBD-associated eQTL unique to diseased tissue had distinct regulatory and functional characteristics with increased effect sizes. Together, these highlight the importance of eQTL studies in diseased tissue for understanding functional consequences of genetic variants, and elucidating molecular mechanisms and regulation of key genes involved in IBD.

genomics↗

bioRxiv2022

Quorum sensing peptidic inhibitor rescue host immune system eradication: a novel QS infectivity mechanism

Subverting the host immune system is a major task for any given pathogen to assure its survival and proliferation. For the opportunistic human pathogen Bacillus cereus (Bc), immune evasion enables the establishment of potent infections. In various species of the Bc group, the pleiotropic regulator PlcR and its cognate cell-cell signaling peptide PapR7 regulates virulence genes expression in response to fluctuations in population density, i.e., a quorum-sensing (QS) system. However, how QS exerts its effects during infections, and whether PlcR confers the immune evading ability remain unclear. Herein, we report how interception of the QS communication in Bc obliterates the ability to control the host immune system. Here we designed a peptide-based QS inhibitor that suppresses PlcR-dependent virulence factor expression and attenuates Bc infectivity in mouse models. We demonstrate that the QS peptidic inhibitor blocks host immune system-mediated eradication by reducing the expression of PlcR-regulated major toxins. Our findings provide the first evidence that Bc infectivity is regulated by QS circuit mediated destruction of the host immunity, thus reveal a new strategy to limit Bc virulence and enhance host defense. This peptidic quorum-quenching agent constitutes readily accessible chemical tool for studying how other pathogen QS systems modulate host immunity and forms a basis for development of anti-infective therapeutics.

microbiology↗

bioRxiv2022

In silico, biochemical, and in vitro analysis of silvestrol binding to the DEAD box RNA helicase eIF4A reveals broad anti-pathogen potential of rocaglates across the eukaryotic tree of life

Selective inhibition of eukaryotic initiation factor 4A (eIF4A), an RNA helicase, has been proposed as a strategy to fight pathogens. Plant-derived rocaglates exhibit some of the highest specificities among eIF4A inhibitors. Sensitivity to rocaglates is determined by key amino acid (aa) residues mediating reversible clamping of the eIF4A:RNA complex. To date, no comprehensive assessment of eIF4A sensitivity to rocaglates across the eukaryotic tree of life has been performed to determine their anti-pathogenic potential. We performed an in silico analysis of the substitution patterns of six aa residues in eIF4A1 critical to rocaglate binding (human positions 158, 159, 163, 192, 195, 199), uncovering 35 pattern variants among 365 eIF4As sequenced to date. In silico molecular docking analysis of the eIF4A:RNA:rocaglate complexes of the 35 variants, modeled in a human eIF4A environment, and in vitro thermal shift assays with recombinantly expressed human eIF4A mutants, representing select natural and artificial variants, revealed that sensitivity to a natural or one of two synthetic rocaglates--silvestrol, CR-1-31-B, or zotatifin--was associated with lower inferred binding energies and higher melting temperature shifts. Helicase activities were comparable across variants and independent of sensitivity to rocaglates. In vitro testing with silvestrol validated predicted resistance based on position 163 substitutions in Caenorhabditis elegans and Leishmania amazonensis and predicted sensitivity in Aedes sp., Schistosoma mansoni, Trypanosoma brucei, Plasmodium falciparum, and Toxoplasma gondii. Our analysis shows resistance to rocaglates emerging in disparate eukaryotic clades pointing to resistance being a selective neutral trait except in rocaglate-producing Aglaia plants and their fungal parasite Ophiocordyceps. The analysis further revealed the possibility of targeting important insect, plant, animal, and human pathogens including Galleria mellonella, Ustilago maydis, Babesia ovata, and Cryptosporidium sp., with rocaglates. Finally, combined docking and thermal shift analyses might help design novel synthetic rocaglate derivatives or alternative eIF4A inhibitors to fight pathogens. Author SummaryIn the ongoing search for novel ways to fight non-viral and non-bacterial pathogens, targeting translation--the universal process of protein synthesis--to inhibit growth and cell proliferation has emerged as an attractive strategy. Here, we focused on the potential of rocaglates, a group of plant-derived compounds, to inhibit an early step in translation mediated by a RNA helicase called eIF4A. We performed a comprehensive analysis of eIF4A sequence variants to determine their potential sensitivities to rocaglates, especially in pathogens of prokaryotic, fungal, or animal origin. We complemented this in silico analysis with enzyme-based in vitro and whole pathogen in vivo experiments to confirm the sensitivity or resistance to rocaglates of specific variants of eIF4A. Our analysis provides the first comprehensive picture of rocaglate sensitivity among pathogens and establishes targeting important insect, plant, animal, and human pathogens such as wax moth larvae, a major parasite of honey bees, corn smut, a widely distributed fungal disease, Babesia, a livestock parasite that causes anemia and babesiois, and Cryptosporidium, the causative organism of cryptosporidiosis in humans, with rocaglates as a viable anti-pathogen strategy.

molecular biology↗

bioRxiv2022

Genetic mapping of APP and amyloid-β biology modulation by trisomy 21

Individuals who have Down syndrome frequently develop early onset Alzheimers disease, a neurodegenerative condition caused by the build-up of aggregated amyloid-{beta} and tau proteins in the brain. Amyloid-{beta} is produced by APP, a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimers disease in these individuals. Here we use a combination of next-generation mouse models of Down syndrome (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid-{beta} accumulation (AppNL-F) to determine how chromosome 21 genes other than APP modulate APP/amyloid-{beta} in the brain when in three copies. We demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid-{beta} accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid-{beta} accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2. Thus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid-{beta} in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD-DS compared to those who have familial AD caused by triplication of APP.

neuroscience↗