International Immunopharmacology, Journal Year: 2024, Volume and Issue: 130, P. 111748 - 111748
Published: March 1, 2024
Language: Английский
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 24, 2025
Genetic association studies provide a unique tool for identifying causal links from genes to human traits and diseases. However, it is challenging determine the biological mechanisms underlying most associations, we lack genome-scale approaches inferring mechanistic pathways cellular functions traits. Here propose new bridge this gap by combining quantitative estimates of gene-trait relationships loss-of-function burden tests with gene-regulatory connections inferred Perturb-seq experiments in relevant cell types. By these two forms data, aim build graphs which directional associations trait can be explained their regulatory effects on programs or direct trait. As proof-of-concept, constructed graph gene hierarchy that jointly controls three partially co-regulated blood We perturbation trait-relevant types, coupled gene-level effect sizes traits, between genetics biology.
Language: Английский
Citations
0
Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16
Published: March 18, 2025
In the practice of clinical rheumatology, identifying individuals at higher risk to develop a chronic inflammatory disease based on their genetic profiles remains major wish.In case axial spondyloarthritis (axSpA), (1) strong association with HLA-B27 may well fulfil this expectation but vast prevalence allele in general population makes unsuitable for early diagnosis. With better tools available, clinicians tailor more effective therapeutic interventions, molecular pathways involved.EQTLs are genomic loci that modulate expression genes. Notably, these factors prevalently non-coding variants can act across cell types and states.(2) The most common method analyzing such impact is directly assay levels RNA produced from gene interest connection specific variant, done single transcript level via quantitative real-time PCR (qRT-PCR), or transcriptome-wide manner sequencing (RNA-seq) methodologies (3). Therefore, eQTLs validated functional effects differential genes, linked ways similar GWAS variants. There crucial steps must be followed process eQTL data, including quality control, mean aggregation, covariate correlation procedures, multiple testing corrections (4).It critical sort approach map context link direct contribution regulatory pathogenesis (5).EQTLs classified into two main types: cis-eQTLs, which affect genes located nearby same chromosome, trans-eQTLs, influencing situated far away genome different chromosomes. It's not trivial identify indicative variations really contributing mechanisms.For mapping provide insights, changes assayed conditions relevant (6). specificity it's pivotal concept because transcriptome its mechanisms dynamic very frequently contextdependent (7). Further, seminal studies have demonstrated only detected certain upon stimulation, introducing response (8), connect disease-relevant treatments variation. Response power show how variation might contribute activated conditions, as stimulus shown osteoarthritis (with cartilage matrix breakdown product, fibronectin fragment), allowing investigation stages disease. (9,10). It has been also associations limited overlap (11).The activity likely active following immune activation, it occurs axSpA.Several works proven significantly associated processes (12,13). axSpA, previously identified ankylosing spondylitis, involved bone remodelling (14,15). Back 2016, Ellinghaus colleague published cross-disease study where they simultaneously investigated landscape pleiotropy five clinically related psoriasis, Crohn's disease, primary sclerosing cholangitis, ulcerative colitis. authors were able new coding Fc Gamma Receptor IIa (FCGR2A), Endoplasmic reticulum aminopeptidase 2 (ERAP2), tyrosine-protein kinase (TYK2) fucosyltransferase (FUT2) shared by diseases (16). Very importantly, IL23R gene, encodes receptor interleukin 23 (IL23R) potential influence susceptibility although no convincing arising SNPS rs11209032 observed transcription either (and cognate IL12RB2) (17). On matter, libraries generation described Fairfax et al. monocytes helpful, highly therefore (8). More recently, Roberts colleagues found an intergenic SNP IL23R-IL12RB2 region had effect despite apparent regulation mRNA expression, proportion IFN-γ+ CD4+ T-cells was increased homozygote subjects carrying genotype 'A/A' (18). other acting locus identification axSpA help researchers shedding light pathophysiology highlighting targets.From perspective, Brown reported eQTLs, comprehensive analysis performed cells obtained peripheral blood patients (19). A total nine loci, Runt-related factor 3 (RUNX3), Interleukin 7 (IL7R, encoding IL-7Ra subunit), ETS proto-oncogene 1 (ETS1, ETS2) B3GNT2 (previously AS ( 14)), showed chromatin interaction, open profile, peaks histone marks (such H3K4me3 H3K27ac) enhancer (eRNA) peaks, them overlapped types. allele-specific differences ATAC-seq signal (Assay Transposase-Accessible Chromatin using regions) (20) GWAS-associated SNP, rs4672505, abundance B3GNT2, poly-Nacetyllactosamine synthase enzyme important modulating T activation cancer (21). reduction caused reduced openness locus. suggest higher-order structures, looping event between distal B3GNT2. (19) 2018, group Professor Gaffney QTLs accessibility human macrophages exposed stimuli IFNγ, Salmonella IFNγ + Salmonella. Understanding binding factors, altering enhancers behaviours during central untangling architecture disease-associated (22) so, strategies mediate axSpA).Single (sc) technology revolutionary field biology genomics, measuring molecules per cell, detecting transcriptomic unprecedented scale resolution (23,24). Thanks development sc-eQTL models cell-state-specific now possible define single-cell varies way along trajectories. This already powerful integrating existing knowledge about alleles predicted targets defined cellular context. Sc profiling will affecting magnitude responses together rate timing.( 7) recent linking complex (i.e neurological disorders): 196 eight nervous system thousands having cell-type-specific (25).Transcriptomic just first layer machinery controls functions signalling cell. Other readouts, accessibility, surface proteins, (TCR)/B (BCR) repertoires, measured complement sc resolution. Simone recently Tregs clusters synovial fluid axSpA. Of note, one CD8+ subset expressed cytotoxic markers, Th17-like RORC+ Treg specifically characterized immunomodulatory molecule lymphocyte activating (LAG-3) (26). value patient and/or tissue derived tissue/fluid perform scRNA-seq-based undeniable We think differently: instead treating observations, trajectories treat each own observation gene. Few years ago, Perez work profiled than million circulating multiplexed sc-RNA-seq. Integrating data genotyping typeand context-specific cis-eQTLs systemic lupus erythematosus (SLE) plausible effect. Joint genome-wide results enabled immune-mediated diseases, fine-mapping discovery novel SLE (27). Furthermore, Yazar through population-based segregating function 14 integration autoimmune (including RA, AxSpA) cohorts causal 160 (28). sctranscriptomics offers opportunity expand depth transcriptional regulation, several methodological limitations still remain. Sctechnology exempt batch effects, influenced technical factors. Nevertheless, computational correction methods aim remove thus preventing confounding downstream (29). there rare particular (i.e. neutrophils high RNases) challenging measure, accentuating need improving annotation efficiency, state definitions analysis. standard pipelines lack accurately quantify HLA polymorphic individuals): suggests instances specialized quantification (30).Studying opportunities personalized medicine axSpA.Understanding facilitate therapeutics aimed targeting pathways. As indicated, combined genomics PI (priority index, genetics-led interprets GWASs prioritize disorders) (31). successfully confirmed known pathogenesis, Th17/IL-23 TNF, drug targets, PTGER4, phosphatidylinositol 3-kinase (PI3K)/AKT, NOTCH, ErbB GPCR. variant diseaseassociated benefits. Existing inhibitors study, PI3K currently used treatment lymphoma, could repurposed, optimized combination therapies those synergistically line, Goldmann samples treatment-naïve rheumatoid arthritis (RA). 898 synovium, 1251 blood, Among these, HLA-DPB2 discovered, rs3128921 driving expression. Both correlated severity lympho-myeloid pathotype, indicating immediate aggressive stratification (32).The multimodal approaches we briefly discussed here, consisting assessing interactions, inform interpretation networks targets.EQTLs represent promising frontier research By elucidating connections variation, mechanisms, hold enhance our understanding SpA improve outcomes approaches.Future should focus omics approaches, proteomics metabolomics, create regulation. Recently, Zhao proteome-wide mendelian randomization assess relationships plasma proteins susceptibility, repurpose licensed drugs (33). utility metabolomic integrated indisputed, understand metabolite (34). so-called metabQTLs, discovered levels, add another complexity full picture extreme gain metabolic insights (35). Metabolomics proteiomics analyses widely applied biomarkers discovery: both considered occurring SpA.As anticipated, advancements sc-RNA-seq dissect level, revealing cell-typespecific patterns stratified subgroups (36).However, step, consequences real point. Validating biological assays, CRISPR/Cas9 editing interference clarify (37) providing robust basis (38). evaluation role haplotype (a set determinants inherited together) (39) fundamental evidence support So, perturbing (gene overexpression silencing) CRISPR (CRISPR KO, interferece) (40). chromosome conformation capture techniques (Hi-C, Micro-C Micro Capture C) resolve (41) signals functionally correlate SNPs target explain differenatial (42). Assessing include protein-DNA formation, mediated complexes DNA regions, euchromatin (open chromatin). (40,43) Artificial intelligence (AI) machine learning research, technologies analyze large datasets efficiently, uncovering interactions missed traditional analytical (44). AI predictive integrate genetics, epigenomics, phenotypic anticipate outcomes, optimization therapies.
Language: Английский
Citations
0
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown
Published: July 5, 2024
Abstract Gene regulatory networks (GRNs) govern many core developmental and biological processes underlying human complex traits. Even with broad-scale efforts to characterize the effects of molecular perturbations interpret gene coexpression, it remains challenging infer architecture regulation in a precise efficient manner. Key properties GRNs, like hierarchical structure, modular organization, sparsity, provide both challenges opportunities for this objective. Here, we seek better understand GRNs using new approach simulate their structure model function. We produce realistic network structures novel generating algorithm based on insights from small-world theory, expression stochastic differential equations formulated accommodate modeling perturbations. With these tools, systematically describe knockouts within across finding subset that recapitulate features recent genome-scale perturbation study. deeper analysis exemplar networks, consider future avenues map data cells perturbed unperturbed states, while are critical discover specific interactions, may be sufficient reveal programs.
Language: Английский
Citations
3
International Immunopharmacology, Journal Year: 2024, Volume and Issue: 130, P. 111748 - 111748
Published: March 1, 2024
Language: Английский
Citations
1