Biology subjects

Chao, M. J.

Publications and source records attributed to Chao, M. J..

5 recordsLinked to original sources

bioRxiv2025

Association of ulcerative colitis with atopic dermatitis: identification of shared and unique mechanisms by construction and computational analysis of disease maps

Background and AimsUlcerative colitis (UC) and atopic dermatitis (AD) are immune-mediated inflammatory diseases with limited treatment options. They are known to be related which may explain higher risk of development of UC in patients with AD. The goal of this work is to review and analyse molecular mechanisms of UC in comparison to AD towards insights into UC complexity, potential comorbidities and novel therapies. MethodsWe developed graphical computational models of UC and AD molecular mechanisms (disease maps) by integrating information from over 800 manually curated articles. The maps are available online at https://imi-immuniverse.elixir-luxembourg.org. Disease-specific risk variants and gene expression profiles are visualised to identify signatures specific to UC, and shared with AD. Computational analysis shows key proteins, their interactions and pathways shared between UC and AD. ResultsUC and AD maps include more than 2000 molecular interactions. Systematic computational comparison shows that both disorders exhibit epithelial barrier dysfunction, immune dysregulation involving abnormal Th2, Th1 and ILC response, common inflammatory pathways and biomarkers such as IL-13, IL-4R, IFNG, and IL-18. Visualisation and analysis of omics data demonstrates UC map usability. ConclusionsWe developed the first computational graphic model of UC molecular mechanisms. Its content focuses on mechanisms of epithelial barrier disruption and downstream immune dysregulation through cytokines and other mediators. The comparison of UC to AD mechanisms demonstrates common signalling pathways and biomarkers, and supports potential drug repurposing and treatment options. The workflow can be reused and new findings can be dynamically integrated into the maps. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/650149v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@1c4c80eorg.highwire.dtl.DTLVardef@2a1e66org.highwire.dtl.DTLVardef@131ece3org.highwire.dtl.DTLVardef@b74971_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG

bioinformatics↗

bioRxiv2021

FAN1 nuclease activity affects CAG expansion and age at onset of Huntington's disease

The age at onset of motor symptoms in Huntingtons disease (HD) is driven by HTT CAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier genes from prior genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier onset HD. Nuclease activities of these variants correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion comparable to those observed with complete FAN1 knock out. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.

neuroscience↗

bioRxiv2019

Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia

Apolipoprotein E (APOE) {varepsilon}4 is the strongest genetic risk factor for Alzheimers disease (AD). Although its association with AD is well-established, the impact of APOE {varepsilon}4 on human brain cell function remains unclear. Here we investigated the effects of APOE {varepsilon}4 on several brain cell types derived from human induced pluripotent stem cells and human APOE targeted replacement mice. Gene set enrichment and pathway analyses of whole transcriptome profiles showed that APOE {varepsilon}4 is associated with dysregulation of cholesterol homeostasis in human but not mouse astrocytes and microglia. Elevated matrisome signaling associated with chemotaxis, glial activation and lipid biosynthesis in APOE {varepsilon}4 mixed neuron/astrocyte cultures parallels altered pathways uncovered in cell-type deconvoluted transcriptomic data from APOE {varepsilon}4 glia and AD post-mortem brains. Experimental validation of the transcriptomic findings showed that isogenic APOE {varepsilon}4 is associated with increased lysosomal cholesterol levels and decreased cholesterol efflux, demonstrating decoupled lipid metabolism. APOE {varepsilon}4 glia also secrete higher levels of proinflammatory chemokines, cytokines and growth factors, indicative of glial activation. Thus, APOE {varepsilon}4 induces human glia-specific dysregulation that may initiate AD risk.

neuroscience↗

bioRxiv2019

Genetic overlap between psychiatric disorders and neuropsychiatric symptoms in HD

Huntingtons disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. In general, polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.

genetics↗

bioRxiv2019

Huntington's disease onset is determined by length of uninterrupted CAG, not encoded polyglutamine, and is modified by DNA maintenance mechanisms

The effects of variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from huntingtins polyglutamine segment, dictates the rate at which HD develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the "polyglutamine disorders".

genetics↗