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Through genome-wide association studies (GWAS) and integrated expression quantitative trait locus (eQTL) analyses, numerous susceptibility genes ("eGenes", whose expressions are significantly associated with common variants) associated with systemic lupus erythematosus (SLE) have been identified. Notably, a subset of these eGenes is correlated with disease activity. However, the precise mechanisms through which these genes contribute to the initiation and progression of the disease remain to be fully elucidated. In this investigation, we initially identify SPATS2L as an SLE eGene correlated with disease activity. eSignaling and transcriptomic analyses suggest its involvement in the type I interferon (IFN) pathway. We observe a significant increase in SPATS2L expression following type I IFN stimulation, and the expression levels are dependent on both the concentration and duration of stimulation. Furthermore, through dual-luciferase reporter assays, western blot analysis, and imaging flow cytometry, we confirm that SPATS2L positively modulates the type I IFN pathway, acting as a positive feedback regulator. Notably, siRNA-mediated intervention targeting SPATS2L, an interferon-inducible gene, in peripheral blood mononuclear cells (PBMCs) from patients with SLE reverses the activation of the interferon pathway. In conclusion, our research highlights the pivotal role of SPATS2L as a positive-feedback regulatory molecule within the type I IFN pathway. Our findings suggest that SPATS2L plays a critical role in the onset and progression of SLE and may serve as a promising target for disease activity assessment and intervention strategies.
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Studies have shown that hepatic stellate cells (HSCs) and interleukin-17a (IL-17a) play important roles in liver tumorigenesis. In addition, fibroblast activation protein-α (FAP) has been shown to be a key regulator of hepatic stellate cell activation. In this study, in vivo and in vitro experiments were performed to verify the promoting effects of IL-17a administration, IL-17a overexpression, and FAP upregulation in HSCs on liver fibrosis and liver tumorigenesis. The cleavage under targets & release using nuclease (CUT&RUN) technique was used to verify the binding status of STAT3 to the FAP promoter. The in vitro studies showed that IL-17a activated HSCs and promoted HCC development and progression. FAP and IL-17a overexpression also activated HSCs, promoted HCC cell proliferation and migration, and inhibited HCC cell apoptosis. The in vivo studies suggested that IL-17a and FAP overexpression in HSCs facilitated liver tumor development and progression. The CUT&RUN results indicated that FAP expression was regulated by STAT3, which could bind to the FAP promoter region and regulate its transcription status. We concluded that IL-17a promoted HCC by increasing FAP expression in HSCs via activation of the STAT3 signaling pathway.
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OBJECTIVES: Systemic lupus erythematosus (SLE) is a highly heterogeneous disease, and B cell abnormalities play a central role in the pathogenesis of SLE. Long non-coding RNAs (lncRNAs) have also been implicated in the pathogenesis of SLE. The expression of lncRNAs is finely regulated and cell-type dependent, so we aimed to identify B cell-expressing lncRNAs as biomarkers for SLE, and to explore their ability to reflect the status of SLE critical pathway and disease activity. METHODS: Weighted gene coexpression network analysis (WGCNA) was used to cluster B cell-expressing genes of patients with SLE into different gene modules and relate them to clinical features. Based on the results of WGCNA, candidate lncRNA levels were further explored in public bulk and single-cell RNA-sequencing data. In another independent cohort, the levels of the candidate were detected by RT-qPCR and the correlation with disease activity was analysed. RESULTS: WGCNA analysis revealed one gene module significantly correlated with clinical features, which was enriched in type I interferon (IFN) pathway. Among non-coding genes in this module, lncRNA RP11-273G15.2 was differentially expressed in all five subsets of B cells from patients with SLE compared with healthy controls and other autoimmune diseases. RT-qPCR validated that RP11-273G15.2 was highly expressed in SLE B cells and positively correlated with IFN scores (r=0.7329, p<0.0001) and disease activity (r=0.4710, p=0.0005). CONCLUSION: RP11-273G15.2 could act as a diagnostic and disease activity monitoring biomarker for SLE, which might have the potential to guide clinical management.
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Interferón Tipo I , Lupus Eritematoso Sistémico , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Redes Reguladoras de Genes , Interferón Tipo I/genética , BiomarcadoresRESUMEN
Systemic Lupus Erythematosus (SLE) is a multifactorial autoimmune disease that arises from a dynamic interplay between genetics and environmental triggers. The advent of sophisticated genomics technology has catalyzed a shift in our understanding of disease etiology, spotlighting the pivotal role of non-coding DNA variants in SLE pathogenesis. In this review, we present a comprehensive examination of the non-coding variants associated with SLE, shedding light on their role in influencing disease risk and progression. We discuss the latest methodological advancements that have been instrumental in the identification and functional characterization of these genomic elements, with a special focus on the transformative power of CRISPR-based gene-editing technologies. Additionally, the review probes into the therapeutic opportunities that arise from modulating non-coding regions associated with SLE. Through an exploration of the complex network of non-coding DNA, this review aspires to decode the genetic puzzle of SLE and set the stage for groundbreaking gene-based therapeutic interventions and the advancement of precision medicine strategies tailored to SLE management.
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Age-associated B cells (ABCs) accumulate during infection, aging, and autoimmunity, contributing to lupus pathogenesis. In this study, we screened for transcription factors driving ABC formation and found that zinc finger E-box binding homeobox 2 (ZEB2) is required for human and mouse ABC differentiation in vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with toll-like receptor 7 (TLR7)-driven lupus, ZEB2 is essential for ABC formation and autoimmune pathology. ZEB2 binds to +20-kb myocyte enhancer factor 2b (Mef2b)'s intronic enhancer, repressing MEF2B-mediated germinal center B cell differentiation and promoting ABC formation. ZEB2 also targets genes important for ABC specification and function, including Itgax. ZEB2-driven ABC differentiation requires JAK-STAT (Janus kinase-signal transducer and activator of transcription), and treatment with JAK1/3 inhibitor reduces ABC accumulation in autoimmune mice and patients. Thus, ZEB2 emerges as a driver of B cell autoimmunity.
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Autoinmunidad , Linfocitos B , Diferenciación Celular , Regulación de la Expresión Génica , Lupus Eritematoso Sistémico , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Animales , Humanos , Ratones , Autoinmunidad/genética , Linfocitos B/citología , Linfocitos B/metabolismo , Diferenciación Celular/genética , Linaje de la Célula/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Factores de Transcripción MEF2/genética , Factores de Transcripción MEF2/metabolismo , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo , Haploinsuficiencia , Envejecimiento/inmunología , Modelos Animales de Enfermedad , FemeninoRESUMEN
OBJECTIVE: The diminished expression of microRNA-146a (miR-146a) in systemic lupus erythematosus (SLE) contributes to the aberrant activation of the interferon pathway. Despite its significance, the underlying mechanism driving this reduced expression remains elusive. Considering the integral role of enhancers in steering gene expression, our study seeks to pinpoint the SLE-affected enhancers responsible for modulating miR-146a expression. Additionally, we aim to elucidate the mechanisms by which these enhancers influence the contribution of miR-146a to the activation of the interferon pathway. METHODS: Circular chromosome conformation capture sequencing and epigenomic profiles were applied to identify candidate enhancers of miR-146a. CRISPR activation was performed to screen functional enhancers. Differential analysis of chromatin accessibility was used to identify SLE-dysregulated enhancers, and the mechanism underlying enhancer dysfunction was investigated by analyzing transcription factor binding. The therapeutic value of a lupus-related enhancer was further evaluated by targeting it in the peripheral blood mononuclear cells (PBMCs) of patients with SLE through a CRISPR activation approach. RESULTS: We identified shared and cell-specific enhancers of miR-146a in distinct immune cells. An enhancer 32.5 kb downstream of miR-146a possesses less accessibility in SLE, and its chromatin openness was negatively correlated with SLE disease activity. Moreover, CCAAT/enhancer binding protein α, a down-regulated transcription factor in patients with SLE, binds to the 32.5-kb enhancer and induces the epigenomic change of this locus. Furthermore, CRISPR-based activation of this enhancer in SLE PBMCs could inhibit the activity of interferon pathway. CONCLUSION: Our work defines a promising target for SLE intervention. We adopted integrative approaches to define cell-specific and functional enhancers of the SLE critical gene and investigated the mechanism underlying its dysregulation mediated by a lupus-related enhancer.
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Lupus Eritematoso Sistémico , MicroARNs , Humanos , Cromatina , Cromosomas/metabolismo , Interferones/genética , Leucocitos Mononucleares/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Factores de Transcripción/genéticaRESUMEN
Hepatitis B protein x (HBx) has been reported to promote tumorigenesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), but the mechanism awaits further investigation. In this study, we found that cFAM210A (a circular RNA derived from the third exon of transcript NM_001098801 of the FAM210A gene; CircBase ID: hsa_circ_0003979) can be silenced by HBx. cFAM210A expression was downregulated and negatively correlated with tumorigenesis in patients with HBV-related HCC. Furthermore, cFAM210A reduced the proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, HBx increased the N6-methyladenosine (m6A) level of cFAM210A by promoting the expression of RBM15 (an m6A methyltransferase), thus inducing the degradation of cFAM210A via the YTHDF2-HRSP12-RNase P/MRP pathway. cFAM210A bound to YBX1 and inhibited its phosphorylation, suppressing its transactivation function toward MET. These findings suggest the important role of circular RNAs in HBx-induced hepatocarcinogenesis and identify cFAM210A a potential target in the prevention and treatment of HBV-related HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Transformación Celular Neoplásica , Células Hep G2 , Virus de la Hepatitis B/genética , Neoplasias Hepáticas/patología , ARN Circular/genética , Transactivadores/genética , Transactivadores/metabolismo , Activación Transcripcional , Proteínas Reguladoras y Accesorias Virales/genética , Proteínas Reguladoras y Accesorias Virales/metabolismo , Proteína 1 de Unión a la Caja Y/genética , Proteína 1 de Unión a la Caja Y/metabolismoRESUMEN
Three-dimensional genome organization has been increasingly recognized as an important determinant of the precise regulation of gene expression in mammalian cells, yet the relationship between gene transcriptional activity and spatial subcompartment positioning is still not fully comprehended. Here, we first utilized genome-wide Hi-C data to infer eight types of subcompartment (labeled A1, A2, A3, A4, B1, B2, B3, and B4) in mouse embryonic stem cells and four primary differentiated cell types, including thymocytes, macrophages, neural progenitor cells, and cortical neurons. Transitions of subcompartments may confer gene expression changes in different cell types. Intriguingly, we identified two subsets of subcompartments defined by higher gene density and characterized by strongly looped contact domains, named common A1 and variable A1, respectively. We revealed that common A1, which includes highly expressed genes and abundant housekeeping genes, shows a ~2-fold higher gene density than the variable A1, where cell type-specific genes are significantly enriched. Thus, our study supports a model in which both types of genomic loci with constitutive and regulatory high transcriptional activity can drive the subcompartment A1 formation. Special chromatin subcompartment arrangement and intradomain interactions may, in turn, contribute to maintaining proper levels of gene expression, especially for regulatory non-housekeeping genes.
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OBJECTIVE: Disruption of B cell homeostasis and subsequent dominance of effector B cell subsets are critical for the development of systemic lupus erythematosus (SLE). Revealing the key intrinsic regulators involved in the homeostatic control of B cells has important therapeutic value for SLE. This study was undertaken to determine the regulatory role of the transcription factor Pbx1 in B cell homeostasis and lupus pathogenesis. METHODS: We constructed mice with B cell-specific deletion of Pbx1. T cell-dependent and T cell-independent humoral responses were induced by intraperitoneal injection of nitrophenyl-containing hapten (NP) conjugated to keyhole limpet hemocyanin or NP-Ficoll. The regulatory effects of Pbx1 on autoimmunity were observed in a Bm12-induced lupus murine model. We investigated mechanisms of Pbx1 using RNA sequencing, the cleavage under targets and tagmentation assay, and chromatin immunoprecipitation-quantitative polymerase chain reaction assay. We transduced B cells from SLE patients with plasmids that overexpressed PBX1 to explore the in vitro therapeutic efficacy of PBX1. RESULTS: Pbx1 was specifically down-regulated in autoimmune B cells and negatively correlated with disease activity. The deficiency of Pbx1 in B cells resulted in excessive humoral responses following immunization. In the Bm12-induced lupus model, mice with B cell-specific Pbx1 deficiency displayed enhancements in germinal center responses, plasma cell differentiation, and autoantibody production. Pbx1-deficient B cells had increased survival and proliferative advantages after activation. Pbx1 regulated genetic programs by directly targeting critical components of the proliferation and apoptosis pathways. In SLE patients, PBX1 expression was negatively correlated with effector B cell expansion; when PBX1 expression was enforced, the survival and proliferative capacity of SLE B cells were attenuated. CONCLUSION: Our study reveals the regulatory function and mechanism of Pbx1 in adjusting B cell homeostasis and highlights Pbx1 as a therapeutic target in SLE.
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Autoinmunidad , Lupus Eritematoso Sistémico , Ratones , Animales , Factores de Transcripción/genética , Regulación de la Expresión Génica , Linfocitos B , Factor de Transcripción 1 de la Leucemia de Células Pre-B/genética , Factor de Transcripción 1 de la Leucemia de Células Pre-B/metabolismoRESUMEN
BACKGROUND: At present, the first-line treatment for advanced intrahepatic cholangiocarcinoma (ICC) is gemcitabine combined with cisplatin, but a considerable portion of ICC patients exhibit resistance to gemcitabine. Therefore, finding sensitisers for gemcitabine chemotherapy in ICC patients and predicting molecular markers for chemotherapy efficacy have become urgent needs. METHODS: In this study, PDX models were established to conduct gemcitabine susceptibility tests. The selected PDX tissues of the chemotherapy-sensitive group and drug-resistant group were subjected to transcriptome sequencing and protein chip technology to identify the key genes. Sixty-one ICC patients treated with gemcitabine chemotherapy were recruited for clinical follow-up validation. RESULTS: We found that thrombospondin-1 (TSP1) can predict gemcitabine chemosensitivity in ICC patients. The expression level of TSP1 could reflect the sensitivity of ICC patients to gemcitabine chemotherapy. Functional experiments further confirmed that TSP1 can increase the efficacy of gemcitabine chemotherapy for ICC. A mechanism study showed that TSP1 may affect the intake of oleic acid by binding to the CD36 receptor. CONCLUSIONS: In summary, we found a key molecule-TSP1-that can predict and improve the sensitivity of ICC patients to gemcitabine chemotherapy, which is of great significance for the treatment of advanced cholangiocarcinoma.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Gemcitabina , Desoxicitidina , Colangiocarcinoma/patología , Cisplatino , Biomarcadores , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/patología , Trombospondinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
OBJECTIVE: IRF5 plays a crucial role in the development of lupus. Genome-wide association studies have identified several systemic lupus erythematosus (SLE) risk single-nucleotide polymorphisms (SNPs) enriched in the IRF5 locus. However, no comprehensive genome editing-based functional analysis exists to establish a direct link between these variants and altered IRF5 expression, particularly for enhancer variants. This study was undertaken to dissect the regulatory function and mechanisms of SLE IRF5 enhancer risk variants and to explore the utilization of clustered regularly interspaced short palindromic repeat interference (CRISPRi) to regulate the expression of disease risk gene to intervene in the disease. METHODS: Epigenomic profiles and expression quantitative trait locus analysis were applied to prioritize putative functional variants in the IRF5 locus. CRISPR-mediated deletion, activation, and interference were performed to investigate the genetic function of rs4728142. Allele-specific chromatin immunoprecipitation-quantitative polymerase chain reaction and allele-specific formaldehyde-assisted isolation of regulatory element-quantitative polymerase chain reaction were used to decipher the mechanism of alleles differentially regulating IRF5 expression. The CRISPRi approach was used to evaluate the intervention effect in monocytes from SLE patients. RESULTS: SLE risk SNP rs4728142 was located in an enhancer region, indicating a disease-related regulatory function, and risk allele rs4728142-A was closely associated with increased IRF5 expression. We demonstrated that an rs4728142-containing region could act as an enhancer to regulate the expression of IRF5. Moreover, rs4728142 affected the binding affinity of zinc finger and BTB domain-containing protein 3 (ZBTB3), a transcription factor involved in regulation. Furthermore, in monocytes from SLE patients, CRISPR-based interference with the regulation of this enhancer attenuated the production of disease-associated cytokines. CONCLUSION: These results demonstrate that the rs4728142-A allele increases the SLE risk by affecting ZBTB3 binding, chromatin status, and regulating IRF5 expression, establishing a biologic link between genetic variation and lupus pathogenesis.
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Estudio de Asociación del Genoma Completo , Lupus Eritematoso Sistémico , Humanos , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Sitios de Carácter Cuantitativo , Genómica , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Autoimmune diseases (ADs) are characterized by aberrant generation of autoreactive immune cells and persistent inflammation, leading to tissue destruction. Although common definitive pathogenesis mechanisms of ADs remain elusive, increasing recent evidence has found that non-coding RNAs (ncRNAs) are extensively involved in ADs and AD-related immune responses. Recent advances in the comprehension of biological functions of ncRNAs have greatly evolved the understandings of epigenetic regulation of autoimmunity and ADs. In general, ncRNAs are involved in proliferation, activation, differentiation, apoptosis, and functions of immune cells, promoting or inhibiting immune responses through multiple pathways. Aberrant expression of ncRNAs in immune cells dysregulates immune homeostasis, and has been implicated in a variety of ADs. Therefore, these ncRNAs are promising biomarkers of AD diagnosis and potential therapeutic targets for AD treatment. Clarification of the critical functions and mechanisms for ncRNAs may provide insights into understanding AD pathogenesis and treatment. In this review, we focus on recent studies on the involvement of ncRNAs in autoimmunity and ADs.
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Enfermedades Autoinmunes , ARN Largo no Codificante , Humanos , Autoinmunidad/genética , Epigénesis Genética , ARN no Traducido/genética , Enfermedades Autoinmunes/genética , BiomarcadoresRESUMEN
MicroRNAs (miRNAs) were involved in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. We show here that miR-4461 expression is reduced in liver cancer stem cells (CSCs) and predicts the poor prognosis of HCC patients. Knockdown of miR-4461 enhances the self-renewal and tumorigenicity of liver CSCs. Conversely, forced miR-4461 expression inhibits liver CSCs self-renewal and tumorigenesis. Mechanically, miR-4461 directly targets sirtuin 1 (SIRT1) via binding to its 3'-UTR in liver CSCs. The correlation of miR-4461 and SIRT1 was confirmed in human HCC patients' tissues. Additionally, we found that miR-4461 overexpression hepatoma cells are more sensitive to cisplatin treatment. PDXs also showed that miR-4461 high HCC xenografts are sensitive to cisplatin treatment. Clinical cohort analysis further confirmed that HCC patients with high miR-4461 are benefited more from transcatheter arterial chemoembolization (TACE) treatment. In conclusion, our findings revealed the crucial role of the miR-4461 in liver CSCs expansion and cisplatin response, rendering miR-4461 as an optimal target for the prevention and intervention of HCC.
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BACKGROUND AND AIM: Accumulated evidence highlights the role of metabolites in cancer diagnosis. However, the diagnosis of hepatocellular carcinoma (HCC), especially its early diagnosis, is still very difficult. The main purposes of the study are to explore the comprehensive characteristic metabolites of HCC through an integrated nontargeted metabolomics and transcriptomics approach and evaluate the diagnostic value of some metabolic changes in HCC. METHODS: Dysregulated metabolites and pathways in HCC were identified by nontargeted metabolomics analysis of 72 pairs of matched liver tissues, including HCC tissue (HCT) and adjacent noncancerous tissue (ANT). Meanwhile, to ensure the reliability of the results, metabolic enzymes were quantified at the mRNA level by RNA sequencing. To facilitate the utilization of this information, a diagnostic model was developed based on binary logistic regression using 63 HCC serum samples collected from the aforementioned 72 patients and 40 noncancer serum samples. RESULTS: The results showed that 267 metabolites were significantly altered in HCT. These differential metabolites binding to related differential metabolic enzyme genes were enriched in 14 metabolic pathways. And combination of 5-oxoproline, taurocholenate sulfate, and maltose could be used as a novel candidate early serum diagnostic marker for HCC. CONCLUSIONS: We profiled the metabolic features of HCC and found global biochemical pathway aberration. The diagnostic potential of differential metabolites found in serum tissues, further validated in liver samples, showed that 5-oxoproline, taurocholenate sulfate, and maltose combination had a high accuracy for hepatocellular carcinoma detection, especially for alpha fetoprotein negative patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Reproducibilidad de los Resultados , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Metaboloma , SulfatosRESUMEN
Background: Sleep quality has been always an important problem for patients after hepatectomy. The main purpose of the study is to investigate the effects of early ambulation on sleep quality in patients after liver resection via a quantitative study. Methods: Patients undergoing liver tumor resection were randomly divided into two groups, and the Pittsburgh Sleep Quality Index (PSQI) was used to assess the postoperative activities and sleep quality. Results: Patients who started early ambulation after liver resection had significantly better sleep quality, faster recovery of gastrointestinal function and shorter lengths of postoperative hospital stay compared with the control group. And there was no significant difference in the incidence of postoperative complications between the two groups. Conclusion: Early standardized physical activities are feasible for patients after liver resection, which can significantly improve patient's sleep quality, reduce patient's pain and the nursing workload, and achieve rapid recovery.
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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death, and the prognosis varies due to its high heterogeneity, systematic evaluation of HCC is mainly based on genomic and transcriptomic features, metabolomics-based classification has yet to be reported. Here we performed RNA-seq on 50 paired samples and metabolomics analysis on 72 paired samples of both normal and tumor tissues from HCC patients. Through unsupervised hierarchical cluster analysis with train and test data sets, metabolic and gene expression signatures were identified. We found that most fluxes related to glutamate are attenuated, except for the glutamate-proline pathway. Three subgroups were identified with distinct survival, clinical observations, and metabolic/gene signatures. S1 is characterized by a relatively poor prognosis, a low concentration of the degradation products of phosphatidylcholine and phosphatidylethanolamine, an enrichment of specific genes related to focal adhesion, and an upregulation of genes on chromosome 6q27. Beyond commonly downregulated metabolites, S2 tumors are largely characterized by few alterations in metabolites and genes, as well as low incidence of mutations/loss of heterozygosity, the metabolite signature of this group consists of hexoses and their phosphates, and the prognosis is the best, with a 5-year survival rate of greater than 80%. S3 is characterized by the worst survival (an approximately 20% 5-year survival rate), unsaturated fatty acid metabolites, an upregulation of specific genes involved in metastasis, and an upregulation of genes on chromosome 1q21. The metabolite-based classifications are more stable and reproducible, with each subgroup characterized by a distinct molecular signature and disease prognosis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Regulación Neoplásica de la Expresión Génica , Glutamatos/genética , Glutamatos/metabolismo , Humanos , Neoplasias Hepáticas/patología , Metabolómica , Fosfatos/metabolismo , Fosfatidilcolinas , Fosfatidiletanolaminas , Prolina/genéticaRESUMEN
DNA methylation plays a pivotal role in the development and progression of tumors. However, studies focused on the dynamic changes of DNA methylation in the development of hepatocellular carcinoma (HCC) are rare. To systematically illustrate the dynamic DNA methylation alternation from premalignant to early-stage liver cancer with the same genetic background, this study enrolled 5 HBV-related patients preceded with liver cirrhosis, pathologically identified as early-stage HCC with dysplastic nodules. Liver fibrosis tissues, dysplastic nodules and early HCC tissues from these patients were used to measure DNA methylation. Here, we report significant differences in the DNA methylation spectrum among the three types of tissues. In the early stage of HCC, DNA hypermethylation of tumor suppressor genes is predominant. Additionally, DNA hypermethylation in the early stage of HCC changes the binding ability of transcription factor TP53 to the promoter of tumor suppressor gene ZNF334, and inhibits the expression of ZNF334 at the transcription level. Furthermore, through a series of in vivo and in vitro experiments, we have clarified the exacerbation effect of tumor suppressor gene ZNF334 deletion in the occurrence of HCC. Combined with clinical data, we found that the overall survival and relapse-free survival of patients with high ZNF334 expression are significantly longer. Thus, we partly elucidated a sequential alternation of DNA methylation modification during the occurrence of HCC, and clarified the biological function and regulatory mechanism of the tumor suppressor gene ZNF334, which is regulated by related DNA methylation sites. Our study provides a new target and clinical evidence for the early diagnosis and sheds light on the precise treatment of liver cancer.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patología , Proteínas Portadoras , ADN/metabolismo , Metilación de ADN/genética , Genes Supresores de Tumor , Humanos , Cirrosis Hepática/genética , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/genéticaRESUMEN
Despite strong evidence that human genetic variants affect the expression of many key transcription factors involved in autoimmune diseases, establishing biological links between non-coding risk variants and the gene targets they regulate remains a considerable challenge. Here, we combine genetic, epigenomic, and CRISPR activation approaches to screen for functional variants that regulate IRF8 expression. We demonstrate that the locus containing rs2280381 is a cell-type-specific enhancer for IRF8 that spatially interacts with the IRF8 promoter. Further, rs2280381 mediates IRF8 expression through enhancer RNA AC092723.1, which recruits TET1 to the IRF8 promoter regulating IRF8 expression by affecting methylation levels. The alleles of rs2280381 modulate PU.1 binding and chromatin state to regulate AC092723.1 and IRF8 expression differentially. Our work illustrates an integrative strategy to define functional genetic variants that regulate the expression of critical genes in autoimmune diseases and decipher the mechanisms underlying the dysregulation of IRF8 expression mediated by lupus risk variants.
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Enfermedades Autoinmunes , ARN Largo no Codificante , Enfermedades Autoinmunes/genética , Metilación de ADN/genética , Humanos , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Oxigenasas de Función Mixta/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Secuencias Reguladoras de Ácidos NucleicosRESUMEN
BACKGROUND: Serum iron status has been reported as associated with primary liver cancer (PLC) risk. However, whether iron status plays a role in the development of PLC remains inconclusive. METHODS: Genetic summary statistics of the four biomarkers (serum iron, ferritin, transferrin saturation, and transferrin) of iron status and PLC were retrieved from two independent genome-wide association studies (GWAS) that had been performed in European populations. Two-sample univariate and multivariate Mendelian randomization (MR) analyses were conducted to determine the causal link between iron status and PLC risk. RESULTS: No significant horizontal pleiotropy was detected for the four biomarkers according to the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test. No evidence of between-single nucleotide polymorphism (SNP) heterogeneity and directional pleiotropy was detected by the Cochran's Q test and MR-Egger regression for serum iron, ferritin, and transferrin. For transferrin saturation, although no heterogeneity was detected, the directional pleiotropy was significant (P value for intercept of MR-Egger regression =0.033). Univariate MR estimates based on inverse variance weighting (IVW) method suggested that there was no causal link between serum iron [odds ratio (OR) =0.71, 95% confidence interval (CI): 0.45 to 1.11], ferritin (OR =0.56, 95% CI: 0.16 to 2.04), and transferrin (OR =0.91, 95% CI: 0.72 to 1.15) and PLC risk. We found a significant causal relationship between transferrin saturation and PLC risk (OR =0.45, 95% CI: 0.22 to 0.90), although this link was non-significant in multivariate MR analysis. CONCLUSIONS: There might be no causal relationship between iron status and PLC risk. However, data from larger sample size and people with different ethnic background were needed to further validate our findings.
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This study was to investigate the effects of chitosan-chelated zinc on ileal microbiota, inflammatory response, and barrier function in weaned piglets challenged with Escherichia coli K88. Piglets of the chitosan-chelated zinc treatment (Cs-Zn; 100 mg zinc + 766 mg chitosan/kg basal diet, from chitosan-chelated zinc) and the chitosan treatment (CS, 766 mg chitosan/kg basal diet) had significantly increased ileal villus height and the ratio of villi height to crypt depth. CS-Zn group piglets had a higher abundance of Lactobacillus in the ileal digesta, while the abundance of Streptococcus, Escherichia shigella, Actinobacillus, and Clostridium sensu stricto 6 was significantly decreased. The concentrations of propionate, butyrate, and lactate in the CS-Zn group piglets were significantly increased, while the pH value was significantly decreased. Furthermore, the concentrations of IL-1ß, TNF-α, MPO, and INF-γ in the ileal mucosa of the CS-Zn and the H-ZnO group (pharmacological dose of 1600 mg Zn/kg basal diet, from ZnO) were significantly lower than those of the control group fed with basal diet, and the mRNA expression of TLR4, MyD88, and NF-κB of the CS-Zn group was also reduced. In addition, the mRNA expression of IGF-1 was increased, the protein expression of occludin and claudin-1 was enhanced, while the mRNA expression of caspase 3 and caspase 8 was decreased in the CS-Zn group. These results suggest CS-Zn treatment could help modulate the composition of ileal microbiota, attenuate inflammatory response, and maintain the intestinal function in weaned piglets challenged with Escherichia coli K88. KEY POINTS: ⢠Chitosan-chelated zinc significantly modulated ileal microbiota. ⢠Chitosan-chelated zinc can improve ileal health. ⢠The ileal microbiota plays an important role in host health.