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1.
Nat Commun ; 14(1): 1208, 2023 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-36869052

RESUMO

Genetic sharing is extensively observed for autoimmune diseases, but the causal variants and their underlying molecular mechanisms remain largely unknown. Through systematic investigation of autoimmune disease pleiotropic loci, we found most of these shared genetic effects are transmitted from regulatory code. We used an evidence-based strategy to functionally prioritize causal pleiotropic variants and identify their target genes. A top-ranked pleiotropic variant, rs4728142, yielded many lines of evidence as being causal. Mechanistically, the rs4728142-containing region interacts with the IRF5 alternative promoter in an allele-specific manner and orchestrates its upstream enhancer to regulate IRF5 alternative promoter usage through chromatin looping. A putative structural regulator, ZBTB3, mediates the allele-specific loop to promote IRF5-short transcript expression at the rs4728142 risk allele, resulting in IRF5 overactivation and M1 macrophage polarization. Together, our findings establish a causal mechanism between the regulatory variant and fine-scale molecular phenotype underlying the dysfunction of pleiotropic genes in human autoimmunity.


Assuntos
Doenças Autoimunes , Proteínas de Ligação a DNA , Fatores Reguladores de Interferon , Humanos , Alelos , Autoimunidade , Cromatina , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
2.
iScience ; 24(12): 103468, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34888502

RESUMO

Context-specific activities of transcription regulators (TRs) in the nucleus modulate spatiotemporal gene expression precisely. Using the largest ChIP-seq data and chromatin loops in the human K562 cell line, we initially interrogated TR cooperation in 3D chromatin via a graphical model and revealed many known and novel TRs manipulating context-specific pathways. To explore TR cooperation across broad tissue/cell types, we systematically leveraged large-scale open chromatin profiles, computational footprinting, and high-resolution chromatin interactions to investigate tissue/cell type-specific TR cooperation. We first delineated a landscape of TR cooperation across 40 human tissue/cell types. Network modularity analyses uncovered the commonality and specificity of TR cooperation in different conditions. We also demonstrated that TR cooperation information can better interpret the disease-causal variants identified by genome-wide association studies and recapitulate cell states during neural development. Our study characterizes shared and unique patterns of TR cooperation associated with the cell type specificity of gene regulation in 3D chromatin.

3.
Cell Discov ; 7(1): 121, 2021 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-34930913

RESUMO

Ovarian cancer survival varies considerably among patients, to which germline variation may also contribute in addition to mutational signatures. To identify genetic markers modulating ovarian cancer outcome, we performed a genome-wide association study in 2130 Chinese ovarian cancer patients and found a hitherto unrecognized locus at 3p26.1 to be associated with the overall survival (Pcombined = 8.90 × 10-10). Subsequent statistical fine-mapping, functional annotation, and eQTL mapping prioritized a likely casual SNP rs9311399 in the non-coding regulatory region. Mechanistically, rs9311399 altered its enhancer activity through an allele-specific transcription factor binding and a long-range interaction with the promoter of a lncRNA BHLHE40-AS1. Deletion of the rs9311399-associated enhancer resulted in expression changes in several oncogenic signaling pathway genes and a decrease in tumor growth. Thus, we have identified a novel genetic locus that is associated with ovarian cancer survival possibly through a long-range gene regulation of oncogenic pathways.

4.
Front Neurosci ; 15: 639527, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33958982

RESUMO

Mapping gene expression profiles to neuroimaging phenotypes in the same anatomical space provides opportunities to discover molecular substrates for human brain functional properties. Here, we aimed to identify cell-type-specific gene modules associated with the regional homogeneity (ReHo) of spontaneous brain activity and their associations with brain disorders. Fourteen gene modules were consistently associated with ReHo in the three datasets, five of which showed cell-type-specific expression (one neuron-endothelial module, one neuron module, one astrocyte module and two microglial modules) in two independent cell series of the human cerebral cortex. The neuron-endothelial module was mainly enriched for transporter complexes, the neuron module for the synaptic membrane, the astrocyte module for amino acid metabolism, and microglial modules for leukocyte activation and ribose phosphate biosynthesis. In enrichment analyses of cell-type-specific modules for 10 common brain disorders, only the microglial module was significantly enriched for genes obtained from genome-wide association studies of multiple sclerosis (MS) and Alzheimer's disease (AD). The ReHo of spontaneous brain activity is associated with the gene expression profiles of neurons, astrocytes, microglia and endothelial cells. The microglia-related genes associated with MS and AD may provide possible molecular substrates for ReHo abnormality in both brain disorders.

5.
Sci Adv ; 6(42)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33055159

RESUMO

Cardiovascular dysfunction is one of the most common complications of long-term cancer treatment. Growing evidence has shown that antineoplastic drugs can increase cardiovascular risk during cancer therapy, seriously affecting patient survival. However, little is known about the genetic factors associated with the cardiovascular risk of antineoplastic drugs. We established a compendium of genetic evidence that supports cardiovascular risk induced by antineoplastic drugs. Most of this genetic evidence is attributed to causal alleles altering the expression of cardiovascular disease genes. We found that antineoplastic drugs predicted to induce cardiovascular risk are significantly enriched in drugs associated with cardiovascular adverse reactions, including many first-line cancer treatments. Functional experiments validated that retinoid X receptor agonists can reduce triglyceride lipolysis, thus modulating cardiovascular risk. Our results establish a link between the causal allele of cardiovascular disease genes and the direction of pharmacological modulation, which could facilitate cancer drug discovery and clinical trial design.


Assuntos
Antineoplásicos , Doenças Cardiovasculares , Neoplasias , Antineoplásicos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/genética , Fatores de Risco de Doenças Cardíacas , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Fatores de Risco
6.
Nucleic Acids Res ; 48(D1): D983-D991, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31598699

RESUMO

Recent advances in genome sequencing and functional genomic profiling have promoted many large-scale quantitative trait locus (QTL) studies, which connect genotypes with tissue/cell type-specific cellular functions from transcriptional to post-translational level. However, no comprehensive resource can perform QTL lookup across multiple molecular phenotypes and investigate the potential cascade effect of functional variants. We developed a versatile resource, named QTLbase, for interpreting the possible molecular functions of genetic variants, as well as their tissue/cell-type specificity. Overall, QTLbase has five key functions: (i) curating and compiling genome-wide QTL summary statistics for 13 human molecular traits from 233 independent studies; (ii) mapping QTL-relevant tissue/cell types to 78 unified terms according to a standard anatomogram; (iii) normalizing variant and trait information uniformly, yielding >170 million significant QTLs; (iv) providing a rich web client that enables phenome- and tissue-wise visualization; and (v) integrating the most comprehensive genomic features and functional predictions to annotate the potential QTL mechanisms. QTLbase provides a one-stop shop for QTL retrieval and comparison across multiple tissues and multiple layers of molecular complexity, and will greatly help researchers interrogate the biological mechanism of causal variants and guide the direction of functional validation. QTLbase is freely available at http://mulinlab.org/qtlbase.


Assuntos
Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Fenótipo , Locos de Características Quantitativas , Característica Quantitativa Herdável , Biologia Computacional/métodos , Genômica/métodos , Humanos , Software , Navegador
7.
Nucleic Acids Res ; 48(D1): D807-D816, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31691819

RESUMO

Genome-wide association studies (GWASs) have revolutionized the field of complex trait genetics over the past decade, yet for most of the significant genotype-phenotype associations the true causal variants remain unknown. Identifying and interpreting how causal genetic variants confer disease susceptibility is still a big challenge. Herein we introduce a new database, CAUSALdb, to integrate the most comprehensive GWAS summary statistics to date and identify credible sets of potential causal variants using uniformly processed fine-mapping. The database has six major features: it (i) curates 3052 high-quality, fine-mappable GWAS summary statistics across five human super-populations and 2629 unique traits; (ii) estimates causal probabilities of all genetic variants in GWAS significant loci using three state-of-the-art fine-mapping tools; (iii) maps the reported traits to a powerful ontology MeSH, making it simple for users to browse studies on the trait tree; (iv) incorporates highly interactive Manhattan and LocusZoom-like plots to allow visualization of credible sets in a single web page more efficiently; (v) enables online comparison of causal relations on variant-, gene- and trait-levels among studies with different sample sizes or populations and (vi) offers comprehensive variant annotations by integrating massive base-wise and allele-specific functional annotations. CAUSALdb is freely available at http://mulinlab.org/causaldb.


Assuntos
Mapeamento Cromossômico , Bases de Dados Genéticas , Doença/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Locos de Características Quantitativas
8.
Sci Adv ; 5(6): eaaw3593, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31183407

RESUMO

Positive transcription elongation factor b (P-TEFb) functions as a central regulator of transcription elongation. Activation of P-TEFb occurs through its dissociation from the transcriptionally inactive P-TEFb/HEXIM1/7SK snRNP complex. However, the mechanisms of signal-regulated P-TEFb activation and its roles in human diseases remain largely unknown. Here, we demonstrate that cAMP-PKA signaling disrupts the inactive P-TEFb/HEXIM1/7SK snRNP complex by PKA-mediated phosphorylation of HEXIM1 at serine-158. The cAMP pathway plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD), and we show that P-TEFb is hyperactivated in mouse and human ADPKD kidneys. Genetic activation of P-TEFb promotes cyst formation in a zebrafish ADPKD model, while pharmacological inhibition of P-TEFb attenuates cyst development by suppressing the pathological gene expression program in ADPKD mice. Our study therefore elucidates a mechanism by which P-TEFb activation by cAMP-PKA signaling promotes cystogenesis in ADPKD.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Rim Policístico Autossômico Dominante/patologia , Fator B de Elongação Transcricional Positiva/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/química , Cistos/metabolismo , Cistos/patologia , Modelos Animais de Doenças , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos Knockout , Fosforilação , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/metabolismo , Fator B de Elongação Transcricional Positiva/antagonistas & inibidores , Fator B de Elongação Transcricional Positiva/genética , Ligação Proteica , Proteínas de Ligação a RNA/metabolismo , Ribonucleoproteínas Nucleares Pequenas/química , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Transdução de Sinais , Canais de Cátion TRPP/deficiência , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismo , Fatores de Transcrição/metabolismo , Peixe-Zebra/metabolismo
10.
Nucleic Acids Res ; 46(W1): W114-W120, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29771388

RESUMO

Genome-wide association studies have generated over thousands of susceptibility loci for many human complex traits, and yet for most of these associations the true causal variants remain unknown. Tissue/cell type-specific prediction and prioritization of non-coding regulatory variants will facilitate the identification of causal variants and underlying pathogenic mechanisms for particular complex diseases and traits. By leveraging recent large-scale functional genomics/epigenomics data, we develop an intuitive web server, GWAS4D (http://mulinlab.tmu.edu.cn/gwas4d or http://mulinlab.org/gwas4d), that systematically evaluates GWAS signals and identifies context-specific regulatory variants. The updated web server includes six major features: (i) updates the regulatory variant prioritization method with our new algorithm; (ii) incorporates 127 tissue/cell type-specific epigenomes data; (iii) integrates motifs of 1480 transcriptional regulators from 13 public resources; (iv) uniformly processes Hi-C data and generates significant interactions at 5 kb resolution across 60 tissues/cell types; (v) adds comprehensive non-coding variant functional annotations; (vi) equips a highly interactive visualization function for SNP-target interaction. Using a GWAS fine-mapped set for 161 coronary artery disease risk loci, we demonstrate that GWAS4D is able to efficiently prioritize disease-causal regulatory variants.


Assuntos
Doenças Genéticas Inatas , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Software , Biologia Computacional/tendências , Genômica/métodos , Humanos , Polimorfismo de Nucleotídeo Único/genética
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