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1.
Am J Hum Genet ; 110(4): 625-637, 2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-36924774

RESUMO

Genome-wide association studies (GWASs) have repeatedly reported multiple non-coding single-nucleotide polymorphisms (SNPs) at 2p14 associated with rheumatoid arthritis (RA), but their functional roles in the pathological mechanisms of RA remain to be explored. In this study, we integrated a series of bioinformatics and functional experiments and identified three intronic RA SNPs (rs1876518, rs268131, and rs2576923) within active enhancers that can regulate the expression of SPRED2 directly. At the same time, SPRED2 and ACTR2 influence each other as a positive feedback signal amplifier to strengthen the protective role in RA by inhibiting the migration and invasion of rheumatoid fibroblast-like synoviocytes (FLSs). In particular, the transcription factor CEBPB preferentially binds to the rs1876518-T allele to increase the expression of SPRED2 in FLSs. Our findings decipher the molecular mechanisms behind the GWAS signals at 2p14 for RA and emphasize SPRED2 as a potential candidate gene for RA, providing a potential target and direction for precise treatment of RA.


Assuntos
Artrite Reumatoide , Sinoviócitos , Humanos , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Proliferação de Células/genética , Células Cultivadas , Cromossomos , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Proteínas Repressoras/genética , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Proteína 2 Relacionada a Actina/metabolismo
2.
Am J Hum Genet ; 110(8): 1266-1288, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37506691

RESUMO

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes.


Assuntos
Resistência à Insulina , Polimorfismo de Nucleotídeo Único , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estudo de Associação Genômica Ampla , Resistência à Insulina/genética , Fatores de Transcrição/genética , Cromatina/genética , Fenótipo , Elementos Facilitadores Genéticos/genética
3.
Hum Mol Genet ; 31(11): 1871-1883, 2022 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34962261

RESUMO

Thyroid dysfunction is a common endocrine disease measured by thyroid-stimulating hormone (TSH) level. Although >70 genetic loci associated with TSH have been reported through genome-wide association studies (GWASs), the variants can only explain a small fraction of the thyroid function heritability. To identify novel candidate genes for thyroid function, we conducted the first large-scale transcriptome-wide association study (TWAS) for thyroid function using GWAS-summary data for TSH levels in up to 119 715 individuals combined with precomputed gene expression weights of six panels from four tissue types. The candidate genes identified by TWAS were further validated by TWAS replication and gene expression profiles. We identified 74 conditionally independent genes significantly associated with thyroid function, such as PDE8B (P = 1.67 × 10-282), PDE10A (P = 7.61 × 10-119), NR3C2 (P = 1.50 × 10-92) and CAPZB (P = 3.13 × 10-79). After TWAS replication using UKBB datasets, 26 genes were replicated for significant associations with thyroid-relevant diseases/traits. Among them, 16 genes were causal for their associations to thyroid-relevant diseases/traits and further validated in differential expression analyses, including two novel genes (MFSD6 and RBM47) that did not implicate in previous GWASs. Enrichment analyses detected several pathways associated with thyroid function, such as the cAMP signaling pathway (P = 7.27 × 10-4), hemostasis (P = 3.74 × 10-4), and platelet activation, signaling and aggregation (P = 9.98 × 10-4). Our study identified multiple candidate genes and pathways associated with thyroid function, providing novel clues for revealing the genetic mechanisms of thyroid function and disease.


Assuntos
Estudo de Associação Genômica Ampla , Transcriptoma , Predisposição Genética para Doença , Humanos , Diester Fosfórico Hidrolases/genética , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a RNA/genética , Glândula Tireoide , Tireotropina/genética , Transcriptoma/genética
4.
Diabetes Obes Metab ; 26(1): 135-147, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37779362

RESUMO

AIM: Genome-wide association studies (GWAS) have identified multiple susceptibility loci associated with insulin resistance (IR)-relevant phenotypes. However, the genes responsible for these associations remain largely unknown. We aim to identify susceptibility genes for IR-relevant phenotypes via a transcriptome-wide association study. MATERIALS AND METHODS: We conducted a large-scale multi-tissue transcriptome-wide association study for IR (Insulin Sensitivity Index, homeostasis model assessment-IR, fasting insulin) and lipid-relevant traits (high-density lipoprotein cholesterol, triglycerides, low-density lipoprotein cholesterol and total cholesterol) using the largest GWAS summary statistics and precomputed gene expression weights of 49 human tissues. Conditional and joint analyses were implemented to identify significantly independent genes. Furthermore, we estimated the causal effects of independent genes by Mendelian randomization causal inference analysis. RESULTS: We identified 1190 susceptibility genes causally associated with IR-relevant phenotypes, including 58 genes that were not implicated in the original GWAS. Among them, 11 genes were further supported in differential expression analyses or a gene knockout mice database, such as KRIT1 showed both significantly differential expression and IR-related phenotypic effects in knockout mice. Meanwhile, seven proteins encoded by susceptibility genes were targeted by clinically approved drugs, and three of these genes (H6PD, CACNB2 and DRD2) have been served as drug targets for IR-related diseases/traits. Moreover, drug repurposing analysis identified four compounds with profiles opposing the expression of genes associated with IR risk. CONCLUSIONS: Our study provided new insights into IR aetiology and avenues for therapeutic development.


Assuntos
Resistência à Insulina , Transcriptoma , Animais , Humanos , Camundongos , LDL-Colesterol , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Resistência à Insulina/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise da Randomização Mendeliana
5.
Ecotoxicol Environ Saf ; 276: 116317, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38615641

RESUMO

We have previously shown that excessive activation of macrophage proinflammatory activity plays a key role in TCE-induced immune liver injury, but the mechanism of polarization is unclear. Recent studies have shown that TLR9 activation plays an important regulatory role in macrophage polarization. In the present study, we demonstrated that elevated levels of oxidative stress in hepatocytes mediate the release of mtDNA into the bloodstream, leading to the activation of TLR9 in macrophages to regulate macrophage polarization. In vivo experiments revealed that pretreatment with SS-31, a mitochondria-targeting antioxidant peptide, reduced the level of oxidative stress in hepatocytes, leading to a decrease in mtDNA release. Importantly, SS-31 pretreatment inhibited TLR9 activation in macrophages, suggesting that hepatocyte mtDNA may activate TLR9 in macrophages. Further studies revealed that pharmacological inhibition of TLR9 by ODN2088 partially blocked macrophage activation, suggesting that the level of macrophage activation is dependent on TLR9 activation. In vitro experiments involving the extraction of mtDNA from TCE-sensitized mice treated with RAW264.7 cells further confirmed that hepatocyte mtDNA can activate TLR9 in mouse peritoneal macrophages, leading to macrophage polarization. In summary, our study comprehensively confirmed that TLR9 activation in macrophages is dependent on mtDNA released by elevated levels of oxidative stress in hepatocytes and that TLR9 activation in macrophages plays a key role in regulating macrophage polarization. These findings reveal the mechanism of macrophage activation in TCE-induced immune liver injury and provide new perspectives and therapeutic targets for the treatment of OMDT-induced immune liver injury.


Assuntos
DNA Mitocondrial , Hepatócitos , Estresse Oxidativo , Receptor Toll-Like 9 , Tricloroetileno , Animais , Camundongos , Hepatócitos/efeitos dos fármacos , Tricloroetileno/toxicidade , Receptor Toll-Like 9/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Células RAW 264.7 , Doença Hepática Induzida por Substâncias e Drogas , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL
6.
Chem Biodivers ; 21(2): e202301949, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38326086

RESUMO

Five new iridoids, valeralides A-E (1-5), two new acyclic monoterpenoids, valeralides F (6) and G (7), together with two known iridoids (8 and 9), were isolated from the roots and rhizomes of Valeriana officinalis var. latifolia. Their structures were elucidated based on 1D and 2D NMR, as well as HR-ESI-MS spectroscopic data. The absolute configuration of compounds 1-4 were elucidated based on electronic circular dichroism (ECD) calculation. In addition, all the isolates were evaluated for their inhibition on nitric oxide production, cytotoxicity and anti-influenza A virus activity.


Assuntos
Rizoma , Valeriana , Estrutura Molecular , Valeriana/química , Iridoides/química , Monoterpenos/análise , Raízes de Plantas/química
7.
BMC Genomics ; 24(1): 340, 2023 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-37340366

RESUMO

BACKGROUND: Oriental river prawn (Macrobrachium nipponense) is one of the most dominant species in shrimp farming in China, which is a rich source of protein and contributes to a significant impact on the quality of human life. Thus, more complete and accurate annotation of gene models are important for the breeding research of oriental river prawn. RESULTS: A full-length transcriptome of oriental river prawn muscle was obtained using the PacBio Sequel platform. Then, 37.99 Gb of subreads were sequenced, including 584,498 circular consensus sequences, among which 512,216 were full length non-chimeric sequences. After Illumina-based correction of long PacBio reads, 6,599 error-corrected isoforms were identified. Transcriptome structural analysis revealed 2,263 and 2,555 alternative splicing (AS) events and alternative polyadenylation (APA) sites, respectively. In total, 620 novel genes (NGs), 197 putative transcription factors (TFs), and 291 novel long non-coding RNAs (lncRNAs) were identified. CONCLUSIONS: In summary, this study offers novel insights into the transcriptome complexity and diversity of this prawn species, and provides valuable information for understanding the genomic structure and improving the draft genome annotation of oriental river prawn.


Assuntos
Palaemonidae , Animais , Humanos , Palaemonidae/genética , Perfilação da Expressão Gênica , Transcriptoma , Processamento Alternativo , Isoformas de Proteínas/genética
8.
BMC Plant Biol ; 23(1): 633, 2023 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-38066415

RESUMO

BACKGROUND: Flower color plays a crucial role in attracting pollinators and facilitating environmental adaptation. Investigating the causes of flower color polymorphism and understanding their potential effects on both ecology and genetics can enhance our understanding of flower color polymorphism in wild plant. RESULTS: In this study, we examined the differences of potential male and female fitness between purple- and yellow- flower individuals in Iris potaninii on the Qinghai-Tibet Plateau, and screened key genes and positively selective genes involved in flower color change. Our results showed that yellow flower exhibited a higher pollen-to-ovule ratio. Yellow flowers were derived from purple flowers due to the loss of anthocyanins, and F3H could be an essential gene affecting flower color variation though expression regulation and sequence polymorphism in this species. Furthermore, our findings suggest that genes positively selected in yellow-flowered I. potaninii might be involved in nucleotide excision repair and plant-pathogen interactions. CONCLUSIONS: These results suggest that F3H induces the flower color variation of Iris potaninii, and the subsequent ecological and additive positive selection on yellow flowers may further enhance plant adaptations to alpine environments.


Assuntos
Gênero Iris , Humanos , Gênero Iris/genética , Gênero Iris/metabolismo , Antocianinas/genética , Antocianinas/metabolismo , Tibet , Polimorfismo Genético , Flores/genética , Flores/metabolismo , Cor , Pigmentação/genética
9.
Cell Biol Toxicol ; 39(4): 1359-1375, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36241925

RESUMO

Application of long non-coding RNAs (lncRNAs) for modulation of breast cancer (BC) has attracted much attention. Here, we probed into the role and underlying mechanism of long intergenic non-coding RNA 01270 (LINC01270) in BC. With the help of bioinformatics tools, we identified laminin subunit alpha 2 (LAMA2) as a BC-related differentially expressed gene to discern the effect of LAMA2 in BC cells. LAMA2 was initially poorly expressed while LINC01270 was highly expressed in BC. BC cells were subsequently treated with sh-LINC01270 or/and sh-LAMA2 for exploration of their regulatory mechanism in BC, which unfolded that LINC01270 inhibition up-regulated LAMA2 and inactivated the MAPK signaling pathway to suppress malignant characteristics of BC cells. Functional assays demonstrated that LINC01270 bound to DNMT1, DNMT3a, and DNMT3b promoted the methylation of CpG islands in LAMA2 promoter and inhibited the LAMA2 expression. Moreover, our data suggested that LAMA2 suppressed MAPK signaling pathway to inhibit BC cell malignant characteristics. The in vitro results were re-produced with the help of the in vivo experimentations. In conclusion, LINC01270 silencing inhibited the methylation of LAMA2 promoter to suppress the activation of MAPK signaling pathway, which subsequently restrained the BC progression. 1, Overexpression of LAMA2 inhibits malignant features of BC cells. 2, LINC01270 promotes LAMA2 promoter methylation by recruiting DNMTs to the LAMA2 promoter region. 3, 5-aza-dc reverses the promotion of LAMA2 promoter methylation by LINC01270. 4, LAMA2 inhibits malignant features of BC cells by suppressing the activation of MAPK signaling pathway.


Assuntos
Neoplasias da Mama , RNA Longo não Codificante , Humanos , Feminino , Neoplasias da Mama/metabolismo , Epigênese Genética/genética , Metilação de DNA/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética , Regulação Neoplásica da Expressão Gênica/genética , Regiões Promotoras Genéticas/genética , Linhagem Celular Tumoral
10.
Chem Res Toxicol ; 35(12): 2271-2284, 2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-36440846

RESUMO

Matrine (MT) is a major bioactive compound extracted from Sophorae tonkinensis. However, the clinical application of MT is relatively restricted due to its potentially toxic effects, especially hepatotoxicity. Although MT-induced liver injury has been reported, little is known about the underlying molecular mechanisms. In this study, transcriptomics and metabolomics were applied to investigate the hepatotoxicity of MT in mice. The results indicated that liver injury occurred when the administration of MT (30 or 60 mg/kg, i.g) lasted for 2 weeks, including dramatically increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), etc. The metabolomic results revealed that steroid biosynthesis, purine metabolism, glutathione metabolism, and pyruvate metabolism were involved in the occurrence and development of MT-induced hepatotoxicity. Further, the transcriptomic data indicated that the downregulation of NSDHL with CYP51, FDFT1, and DHCR7, involved in steroid biosynthesis, resulted in a lower level of cholic acid. Besides, Gstps and Nat8f1 were related to the disorder of glutathione metabolism, and HMGCS1 could be treated as the marker gene of the development of MT-induced hepatotoxicity. In addition, other metabolites, such as taurine, flavin mononucleotide (FMN), and inosine monophosphate (IMP), also made a contribution to the boosting of MT-induced hepatotoxicity. In this work, our results provide clues for the mechanism investigation of MT-induced hepatotoxicity, and several biomarkers (metabolites and genes) closely related to the liver injury caused by MT are also provided. Meanwhile, new insights into the understanding of the development of MT-induced hepatotoxicity or other monomer-induced hepatotoxicity were also provided.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Camundongos , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Matrinas , Transcriptoma , Metabolômica/métodos , Fígado/metabolismo , Glutationa/metabolismo , Esteroides/metabolismo , 3-Hidroxiesteroide Desidrogenases/metabolismo
11.
Neoplasma ; 69(1): 103-112, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34846159

RESUMO

Gastric cancer (GC) is the most frequent malignant tumor in the digestive system, with high metastasis potential and poor prognosis. This study aimed to investigate the prognostic value and biological function of thioredoxin domain-containing protein 9 (TXNDC9) in GC. The expression of TXNDC9 was analyzed based on The Cancer Genome Atlas (TCGA) database. The prognostic value of TXNDC9 was evaluated by Kaplan-Meier curves and Cox regression analysis. The mRNA and protein expression of TXNDC9 were analyzed using quantitative real-time PCR and western blot analysis. The effects of TXNDC9 on GC cell invasion and EMT were assessed in vitro, and its effects on tumorigenesis were confirmed using animal experiments. The activity of the NF-κB signaling pathway was examined by both in vitro and in vivo experiments. TXNDC9 was highly expressed in GC tissues and cell lines. A high level of TXNDC9 was associated with poor overall survival and served as an independent prognostic biomarker in GC patients. The knockdown of TXNDC9 led to restrained GC cell invasion, microtubule formation, and EMT in vitro, and suppressed tumorigenesis in vivo. In addition, the NF-κB signaling pathway was demonstrated to mediate the functional role of TXNDC9 in GC. In conclusion, this study found that high TXNDC9 predicted poor prognosis in GC, and served as an oncogene by enhancing tumor cell invasion and EMT through the NF-κB signaling pathway.


Assuntos
NF-kappa B , Neoplasias Gástricas , Animais , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Prognóstico , Neoplasias Gástricas/genética , Tiorredoxinas
12.
Int J Mol Sci ; 23(12)2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35742899

RESUMO

Gastric cancer (GC) is the fifth most common cancer and the third deadliest cancer in the world, and the occurrence and development of GC are influenced by epigenetics. Methyltransferase-like 3 (METTL3) is a prominent RNA n6-adenosine methyltransferase (m6A) that plays an important role in tumor growth by controlling the work of RNA. This study aimed to reveal the biological function and molecular mechanism of METTL3 in GC. The expression level of METTL3 in GC tissues and cells was detected by qPCR, Western blot and immunohistochemistry, and the expression level and prognosis of METTL3 were predicted in public databases. CCK-8, colony formation, transwell and wound healing assays were used to study the effect of METTL3 on GC cell proliferation and migration. In addition, the enrichment effect of METTL3 on DEK mRNA was detected by the RIP experiment, the m6A modification effect of METTL3 on DEK was verified by the MeRIP experiment and the mRNA half-life of DEK when METTL3 was overexpressed was detected. The dot blot assay detects m6A modification at the mRNA level. The effect of METTL3 on cell migration ability in vivo was examined by tail vein injection of luciferase-labeled cells. The experimental results showed that METTL3 was highly expressed in GC tissues and cells, and the high expression of METTL3 was associated with a poor prognosis. In addition, the m6A modification level of mRNA was higher in GC tissues and GC cell lines. Overexpression of METTL3 in MGC80-3 cells and AGS promoted cell proliferation and migration, while the knockdown of METTL3 inhibited cell proliferation and migration. The results of in vitro rescue experiments showed that the knockdown of DEK reversed the promoting effects of METTL3 on cell proliferation and migration. In vivo experiments showed that the knockdown of DEK reversed the increase in lung metastases caused by the overexpression of METTL3 in mice. Mechanistically, the results of the RIP experiment showed that METTL3 could enrich DEK mRNA, and the results of the MePIP and RNA half-life experiments indicated that METTL3 binds to the 3'UTR of DEK, participates in the m6A modification of DEK and promotes the stability of DEK mRNA. Ultimately, we concluded that METTL3 promotes GC cell proliferation and migration by stabilizing DEK mRNA expression. Therefore, METTL3 is a potential biomarker for GC prognosis and a therapeutic target.


Assuntos
Neoplasias Gástricas , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Transformação Celular Neoplásica , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/patologia
13.
Zhongguo Zhong Yao Za Zhi ; 47(4): 889-896, 2022 Feb.
Artigo em Zh | MEDLINE | ID: mdl-35285187

RESUMO

This study was designed to identify the pathogen causing soft rot of Pinellia ternata in Qianjiang of Hubei province and screen out the effective bactericides, so as to provide a theoretical basis for the control of soft rot of P. ternata. In this study, the pathogen was identified based on molecular biology and physiological biochemistry, followed by the detection of pathogenicity and pathogenicity spectrum via plant tissue inoculation in vitro and the indoor toxicity determination using the inhibition zone method to screen out bactericide with good antibacterial effects. The control effect of the bactericide against P. ternata soft rot was verified by the leave and tuber inoculation in vitro. The phylogenetic tree was constructed based on the 16 S rDNA, dnaX gene, and recA gene sequences, respectively, and the result showed that the pathogen belonged to the same branch as the type strain Dickeya fangzhongdai JS5. The physiological and biochemical tests showed that the pathogen was identical to D. fangzhongdai, which proved that the pathogen was D. fangzhongdai. The pathogenicity test indicated that the pathogen could obviously infect leaves at 24 h and tubers in 3 d. As revealed by the indoor toxicity test, 0.3% tetramycin, 5% allicin, and 80% ethylicin had good antibacterial activities, with EC_(50) values all less than 50 mg·L~(-1). Tests in tissues in vitro showed that 5% allicin exhibited the best control effect, followed by 0.3% tetramycin and 10% zhongshengmycin oligosaccharide, and their preventive effects were better than curative effects. Therefore, 5% allicin can be used as the preferred agent for the control of P. ternata soft rot, and 0.3% tetramycin and 10% zhongshengmycin oligosaccharide as the alternatives. This study has provided a certain theoretical basis for the control of P. ternata soft rot.


Assuntos
Pinellia , Filogenia , Pinellia/química , Folhas de Planta , Tubérculos
14.
Am J Hum Genet ; 102(5): 776-793, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29706346

RESUMO

Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36.12. Dual-luciferase assay and CRISPR/Cas9 experiments demonstrate that rs6426749 acts as a distal allele-specific enhancer regulating expression of a lncRNA (LINC00339) (∼360 kb) via long-range chromatin loop formation and that this loop is mediated by CTCF occupied near rs6426749 and LINC00339 promoter region. Specifically, rs6426749-G allele can bind transcription factor TFAP2A, which efficiently elevates the enhancer activity and increases LINC00339 expression. Downregulation of LINC00339 significantly increases the expression of CDC42 in osteoblast cells, which is a pivotal regulator involved in bone metabolism. Our study provides mechanistic insight into how a noncoding SNP affects osteoporosis by long-range interaction, a finding that could indicate promising therapeutic targets for osteoporosis.


Assuntos
Alelos , Cromossomos Humanos Par 1/genética , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Conformação de Ácido Nucleico , Osteoporose/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genética , Povo Asiático/genética , Sequência de Bases , Densidade Óssea/genética , Osso e Ossos/metabolismo , Sistemas CRISPR-Cas/genética , Linhagem Celular , Cromatina/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Regiões Promotoras Genéticas , Ligação Proteica , Locos de Características Quantitativas/genética , RNA Longo não Codificante/química , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de Transcrição/metabolismo
15.
Bioinformatics ; 36(18): 4739-4748, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32539144

RESUMO

MOTIVATION: CircRNAs are an abundant class of non-coding RNAs with widespread, cell-/tissue-specific patterns. Previous work suggested that epigenetic features might be related to circRNA expression. However, the contribution of epigenetic changes to circRNA expression has not been investigated systematically. Here, we built a machine learning framework named CIRCScan, to predict circRNA expression in various cell lines based on the sequence and epigenetic features. RESULTS: The predicted accuracy of the expression status models was high with area under the curve of receiver operating characteristic (ROC) values of 0.89-0.92 and the false-positive rates of 0.17-0.25. Predicted expressed circRNAs were further validated by RNA-seq data. The performance of expression-level prediction models was also good with normalized root-mean-square errors of 0.28-0.30 and Pearson's correlation coefficient r over 0.4 in all cell lines, along with Spearman's correlation coefficient ρ of 0.33-0.46. Noteworthy, H3K79me2 was highly ranked in modeling both circRNA expression status and levels across different cells. Further analysis in additional nine cell lines demonstrated a significant enrichment of H3K79me2 in circRNA flanking intron regions, supporting the potential involvement of H3K79me2 in circRNA expression regulation. AVAILABILITY AND IMPLEMENTATION: The CIRCScan assembler is freely available online for academic use at https://github.com/johnlcd/CIRCScan. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Epigenômica , RNA Circular , Epigênese Genética , Aprendizado de Máquina , RNA/genética , Curva ROC
16.
Zhongguo Zhong Yao Za Zhi ; 45(14): 3414-3421, 2020 Jul.
Artigo em Zh | MEDLINE | ID: mdl-32726057

RESUMO

Soil microorganisms are one of the important biological indictors of soil quality and can reflct the comprehensive ecological environment characteristics of the soil. The research of soil microbial diversity is the key to know the ecological functions and balance with soil. In this paper, high-throughput sequencing on PCR-amplified 16 S rRNA gene V3-V4 fragments was used to determine the bacterial diversity in rhizosphere soil of A. macrocephala under the treatment with BZJN1 or streptoprofen. The results showed that there were no significant differences of the bacteria in A. macrocephala rhizosphere soil of the streptoprofen treatment group and the biocontrol BZJN1 treatment group. All the soil bacteria was classified into 25 categories,67 classes, 108 orders, 167 families and 271 generas, except some unidentified bacteria. Proteobacteria(30.7%-34.8%) was the dominant phylum, of which Alphaproteobacteria(16.8%-18.5%) was the dominant subgroup. Compared with the control group, the relative abundance of multiple phylums bacteria in the rhizosphere soil of A. macrocephala was significantly changed in the streptoprofen treatment group and the biocontrol BZJN1 treatment group. In addition, RDA analysis showed that there was connection with different environmental factors and microbial communities. The abundance of the three genera in the rhizosphere soil of A. macrocephala was significantly positively correlated with Invertase, Urease and AP. PICRUSt function prediction results showed that BZNJ1 could enhance some bacterial functions and promote the plant growth. Biocontrol is a new type of green and safety control pest method. BZNJ1 significantly enhances some bacterial functions on the basis of effectively preventing root rot of A. macrocephala and promoting plant growth, and has no significant effect on the soil bacterial community structure. All the results can provide theoretical support for popularization of BZNJ1.


Assuntos
Atractylodes , Rizosfera , Bactérias , Solo , Microbiologia do Solo
17.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(8): 903-908, 2020 Aug.
Artigo em Zh | MEDLINE | ID: mdl-32800040

RESUMO

A boy, aged 66 days, was admitted to the hospital due to subcutaneous nodules for 46 days and abdominal distension for 10 days. The main clinical manifestations were loss of adipose tissue, subcutaneous nodules, insulin-resistant diabetes, hypertriglyceridemia, and hepatic steatosis. The boy was diagnosed with congenital generalized lipodystrophy type 1 (CGL1). His condition was improved after administration of middle-chain fatty acid formula milk and insulin injection or oral metformin. Gene testing revealed a homozygous mutation, c.646A>T, in the AGPAT2 gene, and both his parents were carriers of this mutation. This case of CGL1 has the youngest age of onset ever reported in China and multiple subcutaneous nodules as the initial symptom.


Assuntos
Fígado Gorduroso , Resistência à Insulina , Lipodistrofia Generalizada Congênita , Lipodistrofia , Tecido Adiposo , China , Humanos , Lactente , Masculino
18.
J Am Chem Soc ; 141(1): 541-547, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30525560

RESUMO

Perovskite solar cells (PSCs) have reached certified efficiencies of up to 23.7% but suffered from frailness and instability when exposed to ambient atmosphere. Zinc oxide (ZnO), when used as electron transport layer (ETL) on PSCs, gives rise to excellent electronic, optic, and photonic properties, yet the Lewis basic nature of ZnO surface leads to deprotonation of the perovskite layer, resulting in serious degradation of PSCs using ZnO as ETL. Here, we report a simple but effective strategy to convert ZnO surface into ZnS at the ZnO/perovskite interface by sulfidation. The sulfide on ZnO-ZnS surface binds strongly with Pb2+ and creates a novel pathway of electron transport to accelerate electron transfer and reduce interfacial charge recombination, yielding a champion efficiency of 20.7% with improved stability and no appreciable hysteresis. The model devices modified with sulfide maintained 88% of their initial performance for 1000 h under storage condition and 87% for 500 h under UV radiation. ZnS is demonstrated to act as both a cascade ETL and a passivating layer for enhancing the performance of PSCs.

19.
Plant Cell Physiol ; 60(3): 599-611, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496505

RESUMO

Flower color patterns play critical roles in plant-pollinator interactions and represent one of the most common adaptations during angiosperm evolution. However, the molecular mechanisms underlying flower color pattern formation are less understood in non-model organisms. The aim of this study was to identify genes involved in the formation of petal blotches in tree peony (Paeonia suffruticosa) through transcriptome profiling and functional experiments. We identified an R2R3-MYB gene, PsMYB12, representing a distinct R2R3-MYB subgroup, with a spatiotemporal expression pattern tightly associated with petal blotch development. We further demonstrated that PsMYB12 interacts with a basic helix-loop-helix (bHLH) and a WD40 protein in a regulatory complex that directly activates PsCHS expression, which is also specific to the petal blotches. Together, these findings advance our understanding of the molecular mechanisms of pigment pattern formation beyond model plants. They also benefit molecular breeding of tree peony cultivars with novel color patterns and promote germplasm innovation.


Assuntos
Paeonia/metabolismo , Fatores de Transcrição/metabolismo , Aciltransferases/genética , Aciltransferases/metabolismo , Antocianinas/genética , Antocianinas/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Paeonia/genética , Fatores de Transcrição/genética
20.
New Phytol ; 224(4): 1512-1517, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31418867

RESUMO

A widely observed pollinator decline around the world has led to the prediction that terrestrial ecosystems could be disrupted as plant pollination suffers, but declining pollination success has not been tested rigorously in wild plants, and it still remains unclear how pollination success of plant species responds differently in the context of pollinator decline. By viewing the number of seeds per pod as a quantitative measure of successful pollination, we examined seed pods in 4637 herbarium specimens of 109 obligately outcrossing legumes collected over the past century. We found that only 13 species showed significant temporal change with nine of those as an increase. None of the three subfamilies of legumes showed a consistent trend, and the subfamily Papilionoideae with the most specialized flowers, had increasing seed number per pod more often than decreasing. We conclude that legume pollination in China shows no sign of disruption and the effects of plant-pollinator disruption may be more complicated than simplistic predictions have allowed.


Assuntos
Fabaceae/fisiologia , Polinização , Sementes/fisiologia , China , Ecossistema , Flores , Museus
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