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1.
BMC Genomics ; 22(1): 642, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34482814

RESUMO

BACKGROUND: RNA polymerase II plays critical roles in transcription in eukaryotic organisms. C-terminal Domain Phosphatase-like 1 (CPL1) regulates the phosphorylation state of the C-terminal domain of RNA polymerase II subunit B1, which is critical in determining RNA polymerase II activity. CPL1 plays an important role in miRNA biogenesis, plant growth and stress responses. Although cpl1 mutant showes delayed-flowering phenotype, the molecular mechanism behind CPL1's role in floral transition is still unknown. RESULTS: To study the role of CPL1 during the floral transition, we first tested phenotypes of cpl1-3 mutant, which harbors a point-mutation. The cpl1-3 mutant contains a G-to-A transition in the second exon, which results in an amino acid substitution from Glu to Lys (E116K). Further analyses found that the mutated amino acid (Glu) was conserved in these species. As a result, we found that the cpl1-3 mutant experienced delayed flowering under both long- and short-day conditions, and CPL1 is involved in the vernalization pathway. Transcriptome analysis identified 109 genes differentially expressed in the cpl1 mutant, with 2 being involved in floral transition. Differential expression of the two flowering-related DEGs was further validated by qRT-PCR. CONCLUSIONS: Flowering genetic pathways analysis coupled with transciptomic analysis provides potential genes related to floral transition in the cpl1-3 mutant, and a framework for future studies of the molecular mechanisms behind CPL1's role in floral transition.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Flores/fisiologia , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Flores/genética , Regulação da Expressão Gênica de Plantas , Mutação , Fosfoproteínas Fosfatases/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/metabolismo
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 912-916, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487543

RESUMO

MAMLD1 gene has been implicated in 46,XY disorders of sex development (DSD) in recent years. Patients carrying MAMLD1 gene variants showed a "continuous spectrum" of simple micropenis, mild, moderate and severe hypospadias with micropenis, cryptorchidism, split scrotum and even complete gonadal dysplasia. The function of MAMLD1 gene in sexual development has not been fully elucidated, and its role in DSD has remained controversial. This article has reviewed recent findings on the role of the MAMLD1 gene in DSD, including the MAMLD1 gene, its encoded protein, genetic variants, clinical phenotype and possible pathogenic mechanism in DSD.


Assuntos
Proteínas de Ligação a DNA , Transtornos do Desenvolvimento Sexual , Proteínas de Ligação a DNA/genética , Transtornos do Desenvolvimento Sexual/genética , Humanos , Masculino , Mutação , Proteínas Nucleares/genética , Fenótipo , Desenvolvimento Sexual , Fatores de Transcrição/genética
3.
Front Immunol ; 12: 720205, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34504497

RESUMO

Patients with the monogenic immune dysregulatory syndrome autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene, uniformly carry neutralizing autoantibodies directed against type-I interferons (IFNs) and many develop autoimmune pneumonitis, both of which place them at high risk for life-threatening COVID-19 pneumonia. Bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target the SARS-CoV-2 spike protein and block entry of SARS-CoV-2 in host cells. The use of bamlanivimab and etesevimab early during infection was associated with reduced COVID-19-associated hospitalization and death in patients at high risk for progressing to severe disease, which led the US Food and Drug Administration to issue an emergency use authorization for their administration in non-hypoxemic, non-hospitalized high-risk patients. However, the safety and efficacy of these mAbs has not been evaluated in APECED patients. We enrolled two siblings with APECED on an IRB-approved protocol (NCT01386437) and admitted them prophylactically at the NIH Clinical Center for evaluation of mild-to-moderate COVID-19. We assessed the safety and clinical effects of early treatment with bamlanivimab and etesevimab. The administration of bamlanivimab and etesevimab was well tolerated and was associated with amelioration of COVID-19 symptoms and prevention of invasive ventilatory support, admission to the intensive care, and death in both patients without affecting the production of antibodies to the nucleocapsid protein of SARS-CoV-2. If given early in the course of COVID-19 infection, bamlanivimab and etesevimab may be beneficial in APECED and other high-risk patients with neutralizing autoantibodies directed against type-I IFNs.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , COVID-19/tratamento farmacológico , Poliendocrinopatias Autoimunes/tratamento farmacológico , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto , COVID-19/complicações , COVID-19/genética , COVID-19/imunologia , Feminino , Humanos , Interferons/genética , Interferons/imunologia , Masculino , Mutação , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
4.
Zhonghua Gan Zang Bing Za Zhi ; 29(8): 781-787, 2021 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-34517461

RESUMO

Objective: To explore the value of Krüppel-like factor 5 (KLF5), a family member of the zinc finger protein transcription factor, in the diagnosis and prognostic evaluation of hepatocellular carcinoma (HCC). Methods: Cancerous and non-cancerous tissues were collected from 126 cases after HCC surgery by self-matching method with microarray fabrication. Immunohistochemistry was used to analyze the expression of KLF5, clinicopathological characteristics and prognostic value. The sera of 222 cases with chronic liver disease were collected and their KLF5 levels were quantitatively determined by enzyme-linked immunosorbent assay (ELISA). Simultaneously, 40 normal human sera were used as controls to evaluate the value of abnormal KLF5 in the diagnosis and differentiation of benign and malignant liver diseases. T-test, Z-test and χ (2) test were performed on the data. Results: The positive expression rate of KLF5 in the HCC group was 95.2% (120/126), which was significantly higher than the non-cancerous group 38.9% (49/126; χ (2) = 14.385, P < 0.001). KLF5 expression was significantly correlated with TNM stage (stage I 35%, stage II 40%, stage III 74.4%, stage IV 78.1%), tumor size, alpha fetoprotein (AFP) concentration, portal vein embolism, HBV infection and 5-year survival rate. Univariate/multivariate analysis showed that KLF5 high expression was an independent predictor of HCC prognosis. The serum KLF5 level was significantly higher in HCC patients than liver cirrhosis, chronic hepatitis and normal control group (P < 0.001). With the serum KLF5 > 800 ng/ml and AFP > 25 µg/L as limit, the positive rates for HCC diagnosis were 90.48% and 73.81%, respectively, which were lower than the AFP specificity and false positive rate, and was helpful for the differential diagnosis of benign and malignant liver diseases. Conclusion: The overexpression of KLF5 in liver cancer tissues and blood is closely related to the HCC clinical stage and prognosis. Moreover, KLF5 analysis is helpful for HCC diagnosis and differential diagnosis.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais , Carcinoma Hepatocelular/diagnóstico , Humanos , Fatores de Transcrição Kruppel-Like , Neoplasias Hepáticas/diagnóstico , Prognóstico , Fatores de Transcrição , Zinco , Dedos de Zinco , alfa-Fetoproteínas
5.
Nat Commun ; 12(1): 5230, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471129

RESUMO

The role of transcription factors during astrocyte development and their subsequent effects on neuronal development has been well studied. Less is known about astrocytes contributions towards circuits and behavior in the adult brain. Astrocytes play important roles in synaptic development and modulation, however their contributions towards neuronal sensory function and maintenance of neuronal circuit architecture remain unclear. Here, we show that loss of the transcription factor Sox9 results in both anatomical and functional changes in adult mouse olfactory bulb (OB) astrocytes, affecting sensory processing. Indeed, astrocyte-specific deletion of Sox9 in the OB results in decreased odor detection thresholds and discrimination and it is associated with aberrant neuronal sensory response maps. At functional level, loss of astrocytic Sox9 impairs the electrophysiological properties of mitral and tufted neurons. RNA-sequencing analysis reveals widespread changes in the gene expression profiles of OB astrocytes. In particular, we observe reduced GLT-1 expression and consequential alterations in glutamate transport. Our findings reveal that astrocytes are required for physiological sensory processing and we identify astrocytic Sox9 as an essential transcriptional regulator of mature astrocyte function in the mouse OB.


Assuntos
Astrócitos/metabolismo , Bulbo Olfatório/fisiologia , Fatores de Transcrição SOX9/metabolismo , Sensação/fisiologia , Animais , Transportador 2 de Aminoácido Excitatório/genética , Transportador 2 de Aminoácido Excitatório/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios , Fatores de Transcrição SOX9/genética , Fatores de Transcrição
6.
Nat Commun ; 12(1): 5224, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471130

RESUMO

The replication of chromosomes during S phase is critical for cellular and organismal function. Replicative stress can result in genome instability, which is a major driver of cancer. Yet how chromatin is made accessible during eukaryotic DNA synthesis is poorly understood. Here, we report the characterization of a chromatin remodeling enzyme-Yta7-entirely distinct from classical SNF2-ATPase family remodelers. Yta7 is a AAA+ -ATPase that assembles into ~1 MDa hexameric complexes capable of segregating histones from DNA. The Yta7 chromatin segregase promotes chromosome replication both in vivo and in vitro. Biochemical reconstitution experiments using purified proteins revealed that the enzymatic activity of Yta7 is regulated by S phase-forms of Cyclin-Dependent Kinase (S-CDK). S-CDK phosphorylation stimulates ATP hydrolysis by Yta7, promoting nucleosome disassembly and chromatin replication. Our results present a mechanism for how cells orchestrate chromatin dynamics in co-ordination with the cell cycle machinery to promote genome duplication during S phase.


Assuntos
Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Replicação do DNA/fisiologia , Proteínas de Saccharomyces cerevisiae/metabolismo , Adenosina Trifosfatases/metabolismo , Pontos de Checagem do Ciclo Celular , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/genética , DNA/metabolismo , Histonas/metabolismo , Humanos , Fosforilação , Fase S , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Fatores de Transcrição
7.
Nat Commun ; 12(1): 5253, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489471

RESUMO

Genome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we generate gene regulatory annotations in adipocytes and hypothalamic neurons across cellular differentiation stages. We then test variants in 97 obesity-associated loci using a massively parallel reporter assay and identify putatively causal variants that display cell type specific or cross-tissue enhancer-modulating properties. Integrating these variants with gene regulatory information suggests genes that underlie obesity GWAS associations. We also investigate a complex genomic interval on 16p11.2 where two independent loci exhibit megabase-range, cross-locus chromatin interactions. We demonstrate that variants within these two loci regulate a shared gene set. Together, our data support a model where GWAS loci contain variants that alter enhancer activity across tissues, potentially with temporally restricted effects, to impact the expression of multiple genes. This complex model has broad implications for ongoing efforts to understand GWAS.


Assuntos
Adipócitos/fisiologia , Elementos Facilitadores Genéticos , Pleiotropia Genética , Obesidade/genética , Adipócitos/citologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Estudo de Associação Genômica Ampla , Gigantismo/genética , Gigantismo/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Hipotálamo/fisiologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , MAP Quinase Quinase 5/genética , Neurônios/citologia , Neurônios/fisiologia , Polimorfismo de Nucleotídeo Único , Proteínas Quinases/genética , Locos de Características Quantitativas , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Fatores de Transcrição/genética , Transcriptoma
8.
BMC Plant Biol ; 21(1): 412, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496757

RESUMO

BACKGROUND: Fusarium oxysporum f. sp. lycopersici (Fol) is a compendium of pathogenic and non-pathogenic fungal strains. Pathogenic strains may cause vascular wilt disease and produce considerable losses in commercial tomato plots. To gain insight into the molecular mechanisms mediating resistance to Fol in tomato, the aim of our study was to characterize the transcriptional response of three cultivars (CT1, CT2 and IAC391) to a pathogenic (Fol-pt) and a non-pathogenic (Fo-npt) strain of Fo. RESULTS: All cultivars exhibited differentially expressed genes in response to each strain of the fungus at 36 h post-inoculation. For the pathogenic strain, CT1 deployed an apparent active defense response that included upregulation of WRKY transcription factors, an extracellular chitinase, and terpenoid-related genes, among others. In IAC391, differentially expressed genes included upregulated but mostly downregulated genes. Upregulated genes mapped to ethylene regulation, pathogenesis regulation and transcription regulation, while downregulated genes potentially impacted defense responses, lipid transport and metal ion binding. Finally, CT2 exhibited mostly downregulated genes upon Fol-pt infection. This included genes involved in transcription regulation, defense responses, and metal ion binding. CONCLUSIONS: Results suggest that CT1 mounts a defense response against Fol-pt. IAC391 exhibits an intermediate phenotype whereby some defense response genes are activated, and others are suppressed. Finally, the transcriptional profile in the CT2 hints towards lower levels of resistance. Fo-npt also induced transcriptional changes in all cultivars, but to a lesser extent. Results of this study will support genetic breeding programs currently underway in the zone.


Assuntos
Fusarium/patogenicidade , Interações Hospedeiro-Patógeno/genética , Lycopersicon esculentum/genética , Lycopersicon esculentum/microbiologia , Proteínas de Plantas/genética , Cromossomos de Plantas , Colômbia , Resistência à Doença/genética , Etilenos/metabolismo , Regulação da Expressão Gênica de Plantas , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Fatores de Transcrição/genética
9.
BMC Plant Biol ; 21(1): 411, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496770

RESUMO

BACKGROUND: The phytohormone ethylene controls many processes in plant development and acts as a key signaling molecule in response to biotic and abiotic stresses: it is rapidly induced by flooding, wounding, drought, and pathogen attack as well as during abscission and fruit ripening. In kiwifruit (Actinidia spp.), fruit ripening is characterized by two distinct phases: an early phase of system-1 ethylene biosynthesis characterized by absence of autocatalytic ethylene, followed by a late burst of autocatalytic (system-2) ethylene accompanied by aroma production and further ripening. Progress has been made in understanding the transcriptional regulation of kiwifruit fruit ripening but the regulation of system-1 ethylene biosynthesis remains largely unknown. The aim of this work is to better understand the transcriptional regulation of both systems of ethylene biosynthesis in contrasting kiwifruit organs: fruit and leaves. RESULTS: A detailed molecular study in kiwifruit (A. chinensis) revealed that ethylene biosynthesis was regulated differently between leaf and fruit after mechanical wounding. In fruit, wound ethylene biosynthesis was accompanied by transcriptional increases in 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS), ACC oxidase (ACO) and members of the NAC class of transcription factors (TFs). However, in kiwifruit leaves, wound-specific transcriptional increases were largely absent, despite a more rapid induction of ethylene production compared to fruit, suggesting that post-transcriptional control mechanisms in kiwifruit leaves are more important. One ACS member, AcACS1, appears to fulfil a dominant double role; controlling both fruit wound (system-1) and autocatalytic ripening (system-2) ethylene biosynthesis. In kiwifruit, transcriptional regulation of both system-1 and -2 ethylene in fruit appears to be controlled by temporal up-regulation of four NAC (NAM, ATAF1/2, CUC2) TFs (AcNAC1-4) that induce AcACS1 expression by directly binding to the AcACS1 promoter as shown using gel-shift (EMSA) and by activation of the AcACS1 promoter in planta as shown by gene activation assays combined with promoter deletion analysis. CONCLUSIONS: Our results indicate that in kiwifruit the NAC TFs AcNAC2-4 regulate both system-1 and -2 ethylene biosynthesis in fruit during wounding and ripening through control of AcACS1 expression levels but not in leaves where post-transcriptional/translational regulatory mechanisms may prevail.


Assuntos
Actinidia/genética , Etilenos/biossíntese , Proteínas de Plantas/genética , Fatores de Transcrição/genética , Actinidia/metabolismo , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica de Plantas , Liases/genética , Liases/metabolismo , Lycopersicon esculentum/genética , Filogenia , Proteínas de Plantas/metabolismo , Regiões Promotoras Genéticas , Fatores de Transcrição/metabolismo
10.
BMC Bioinformatics ; 22(1): 440, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530727

RESUMO

BACKGROUND: Transcription factors (TFs) are the upstream regulators that orchestrate gene expression, and therefore a centrepiece in bioinformatics studies. While a core strategy to understand the biological context of genes and proteins includes annotation enrichment analysis, such as Gene Ontology term enrichment, these methods are not well suited for analysing groups of TFs. This is particularly true since such methods do not aim to include downstream processes, and given a set of TFs, the expected top ontologies would revolve around transcription processes. RESULTS: We present the TFTenricher, a Python toolbox that focuses specifically at identifying gene ontology terms, cellular pathways, and diseases that are over-represented among genes downstream of user-defined sets of human TFs. We evaluated the inference of downstream gene targets with respect to false positive annotations, and found an inference based on co-expression to best predict downstream processes. Based on these downstream genes, the TFTenricher uses some of the most common databases for gene functionalities, including GO, KEGG and Reactome, to calculate functional enrichments. By applying the TFTenricher to differential expression of TFs in 21 diseases, we found significant terms associated with disease mechanism, while the gene set enrichment analysis on the same dataset predominantly identified processes related to transcription. CONCLUSIONS AND AVAILABILITY: The TFTenricher package enables users to search for biological context in any set of TFs and their downstream genes. The TFTenricher is available as a Python 3 toolbox at https://github.com/rasma774/Tftenricher , under a GNU GPL license and with minimal dependencies.


Assuntos
Biologia Computacional , Fatores de Transcrição , Bases de Dados Factuais , Ontologia Genética , Fatores de Transcrição/genética
11.
Zhongguo Zhong Yao Za Zhi ; 46(15): 3838-3845, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34472257

RESUMO

The longevity mechanism of ginseng(Panax ginseng) is related to its strong meristematic ability. In this paper, this study used bioinformatic methods to identify the members of the ginseng TCP gene family in the whole genome and analyzed their sequence characteristics. Then, quantitative real-time fluorescent PCR was performed to analyze the TCP genes containing elements rela-ted to meristem expression in the taproots, fibrous roots, stems, and leaves. According to the data, this study further explored the expression specificity of TCP genes in ginseng tissues, which facilitated the dissection of the longevity mechanism of ginseng. The ginseng TCP members were identified and analyzed using PlantTFDB, ExPASy, MEME, PLANTCARE, TBtools, MEGA and DNAMAN. The results demonstrated that there were 60 TCP gene family members in ginseng, and they could be divided into two classes: Class Ⅰ and Class Ⅱ, in which the Class Ⅱ possessed two subclasses: CYC-TCP and CIN-TCP. The deduced TCP proteins in ginseng had the length of 128-793 aa, the isoelectric point of 4.49-9.84 and the relative molecular mass of 14.2-89.3 kDa. They all contained the basic helix-loop-helix(bHLH) domain. There are a variety of stress response-related cis-acting elements in the promoter regions of ginseng TCP genes, and PgTCP20-PgTCP24 contained the elements associated with meristematic expression. The transcription levels of PgTCP20-PgTCP24 were high in fibrous roots and leaves, but low in stems, indicating the tissue-specific expression of ginseng TCP genes. The Class Ⅰ TCP members which contained PgTCP20-PgTCP23, may be important regulators for the growth and development of ginseng roots.


Assuntos
Panax , Fatores de Transcrição , Biologia Computacional , Regulação da Expressão Gênica de Plantas , Família Multigênica , Panax/genética , Panax/metabolismo , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
12.
Sheng Wu Gong Cheng Xue Bao ; 37(8): 2595-2602, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472280

RESUMO

Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is a member of orphan nuclear receptors, which is expressed in major tissues and organs of the human body, and plays an important role in the regulation of various biological functions and gene expressions. Recent studies have shown that the expression of NR2F6 was up-regulated in a variety of malignant tumors and showed significant correlations with cancer progression. These findings triggered the widespread interest in understanding the relationship between NR2F6 and cancer development and progression. In addition, the latest studies have underscored that NR2F6 was involved in enhancing antitumor immune responses that could serve as a potential target for immune regulation. This review summarizes the biological functions of NR2F6 and its role in tumors, with the aim to provide new insights into effective cancer therapies.


Assuntos
Neoplasias , Proteínas Repressoras , Fatores de Transcrição , Regulação da Expressão Gênica , Humanos , Neoplasias/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética
13.
Anticancer Res ; 41(9): 4259-4269, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475045

RESUMO

BACKGROUND: Compared to two-dimensional cultures, three-dimensional (3D) cultures have many advantages in cancer studies. Nevertheless, their implementation is unsatisfactory. This study aimed to develop an anchorage-dependent 3D culture model for colorectal cancer research. MATERIALS AND METHODS: Human HCT116, DLD-1 and SW620 colorectal cell lines were cultured in a gelatin sponge, and its applicability for morphological examination was studied. RESULTS: The resulting specimens were suitable for scanning electron microscopy, transmission electron microscopy, and immunohistochemical examination. HCT116 formed smaller structures and migrated through the pores of the sponge. DLD-1 formed larger structures with tight cell-to-cell adhesion. SW620 also formed large structures but small clustered cells tended to attach to the anchorage more favorably. Immunohistochemical staining demonstrated phosphorylated yes-associated protein (YAP) localized near the attachment site in HCT116 cells. CONCLUSION: Because the gelatin sponge provided suitable anchorage and the cultured cells formed distinguishable 3D structures, this method may be useful for further colorectal cancer research.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Técnicas de Cultura de Células/métodos , Neoplasias Colorretais/patologia , Gelatina/química , Tecidos Suporte/química , Fatores de Transcrição/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Neoplasias Colorretais/metabolismo , Células HCT116 , Humanos , Fosforilação
14.
Nat Commun ; 12(1): 5240, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475390

RESUMO

ß-actin is a crucial component of several chromatin remodeling complexes that control chromatin structure and accessibility. The mammalian Brahma-associated factor (BAF) is one such complex that plays essential roles in development and differentiation by regulating the chromatin state of critical genes and opposing the repressive activity of polycomb repressive complexes (PRCs). While previous work has shown that ß-actin loss can lead to extensive changes in gene expression and heterochromatin organization, it is not known if changes in ß-actin levels can directly influence chromatin remodeling activities of BAF and polycomb proteins. Here we conduct a comprehensive genomic analysis of ß-actin knockout mouse embryonic fibroblasts (MEFs) using ATAC-Seq, HiC-seq, RNA-Seq and ChIP-Seq of various epigenetic marks. We demonstrate that ß-actin levels can induce changes in chromatin structure by affecting the complex interplay between chromatin remodelers such as BAF/BRG1 and EZH2. Our results show that changes in ß-actin levels and associated chromatin remodeling activities can not only impact local chromatin accessibility but also induce reversible changes in 3D genome architecture. Our findings reveal that ß-actin-dependent chromatin remodeling plays a role in shaping the chromatin landscape and influences the regulation of genes involved in development and differentiation.


Assuntos
Actinas/metabolismo , Montagem e Desmontagem da Cromatina/fisiologia , Actinas/genética , Animais , Cromatina/metabolismo , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Fibroblastos , Dosagem de Genes , Técnicas de Inativação de Genes , Histonas/metabolismo , Camundongos , Proteínas Nucleares/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Ligação Proteica , Fatores de Transcrição/metabolismo
15.
Nat Commun ; 12(1): 5232, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475402

RESUMO

Disseminated tumor cells often fall into a long term of dormant stage, characterized by decreased proliferation but sustained survival, in distant organs before awakening for metastatic growth. However, the regulatory mechanism of metastatic dormancy and awakening is largely unknown. Here, we show that the epithelial-like and mesenchymal-like subpopulations of breast cancer stem-like cells (BCSCs) demonstrate different levels of dormancy and tumorigenicity in lungs. The long non-coding RNA (lncRNA) NR2F1-AS1 (NAS1) is up-regulated in the dormant mesenchymal-like BCSCs, and functionally promotes tumor dissemination but reduces proliferation in lungs. Mechanistically, NAS1 binds to NR2F1 mRNA and recruits the RNA-binding protein PTBP1 to promote internal ribosome entry site (IRES)-mediated NR2F1 translation, thus leading to suppression of ΔNp63 transcription by NR2F1. Furthermore, ΔNp63 downregulation results in epithelial-mesenchymal transition, reduced tumorigenicity and enhanced dormancy of cancer cells in lungs. Overall, the study links BCSC plasticity with metastatic dormancy, and reveals the lncRNA as an important regulator of both processes.


Assuntos
Neoplasias da Mama/patologia , Fator I de Transcrição COUP/genética , Neoplasias Pulmonares/secundário , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Regiões 5' não Traduzidas , Animais , Neoplasias da Mama/genética , Fator I de Transcrição COUP/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Sítios Internos de Entrada Ribossomal , Pulmão/patologia , Neoplasias Pulmonares/genética , Camundongos , Invasividade Neoplásica , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
16.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445087

RESUMO

The miR-31 host gene (MIR31HG) encodes a long non-coding RNA (LncRNA) that harbors miR-31 in its intron 2; miR-31 promotes malignant neoplastic progression. Overexpression of MIR31HG and of miR-31 occurs during oral squamous cell carcinoma (OSCC). However, the downstream effectors modulated by MIR31HG during OSCC pathogenesis remain unclear. The present study identifies up-regulation of MIR31HG expression during the potentially premalignant disorder stage of oral carcinogenesis. The potential of MIR31HG to enhance oncogenicity and to activate Wnt and FAK was identified when there was exogenous MIR31HG expression in OSCC cells. Furthermore, OSCC cell subclones with MIR31HG deleted were established using a Crispr/Cas9 strategy. RNA sequencing data obtained from cells expressing MIR31HG, cells with MIR31HG deleted and cells with miR-31 deleted identified 17 candidate genes that seem to be modulated by MIR31HG in OSCC cells. A TCGA database algorithm pinpointed MMP1, BMP2 and Limb-Bud and Heart development (LBH) as effector genes controlled by MIR31HG during OSCC. Exogenous LBH expression decreases tumor cell invasiveness, while knockdown of LBH reverses the oncogenic suppression present in MIR31HG deletion subclones. The study provides novel insights demonstrating the contribution of the MIR31HG-LBH cascade to oral carcinogenesis.


Assuntos
Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Bucais/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Humanos , Neoplasias Bucais/patologia , Regulação para Cima
17.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445149

RESUMO

Anthocyanins contribute to the quality and flavour of fruits. They are produced through the phenylpropanoid pathway, which is regulated by specific key genes that have been identified in many species. The dominant anthocyanin forms are reversibly transformed at different pH states, thus forming different colours in aqueous solutions. In plants, anthocyanins are controlled by specific factors of the biosynthetic pathway: light, temperature, phytohormones and transcription factors. Although great progress in research on anthocyanin structures and the regulation of anthocyanin biosynthesis has been made, the molecular regulatory mechanisms of anthocyanin biosynthesis in different plants remain less clear. In addition, the co-regulation of anthocyanin biosynthesis is poorly understood. In this review, we summarise previous findings on anthocyanin biosynthesis, including the biochemical and biological features of anthocyanins; differences in anthocyanin biosynthesis among fruit species, i.e., apple, red pear, and the model plant Arabidopsis thaliana; and the developmental and environmental regulation of anthocyanin accumulation. This review reveals the molecular mechanisms underlying anthocyanin biosynthesis in different plant species and provides valuable information for the development of anthocyanin-rich red-skinned and red-fleshed apple and pear varieties.


Assuntos
Antocianinas/metabolismo , Malus/metabolismo , Pyrus/metabolismo , Antocianinas/genética , Vias Biossintéticas , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica de Plantas , Malus/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Pyrus/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445164

RESUMO

Powerful bioinformatics tools have provided a wealth of novel miRNA-transcription factor networks crucial in controlling gene regulation. In this review, we focus on the biological functions of miRNAs targeting ZNF521, explaining the molecular mechanisms by which the dysregulation of this axis contributes to malignancy. ZNF521 is a stem cell-associated co-transcription factor implicated in the regulation of hematopoietic, neural, and mesenchymal stem cells. The aberrant expression of ZNF521 transcripts, frequently associated with miRNA deregulation, has been detected in several tumors including pancreatic, hepatocellular, gastric, bladder transitional cell carcinomas as well as in breast and ovarian cancers. miRNA expression profiling tools are currently identifying a multitude of miRNAs, involved together with oncogenes and TFs in the regulation of oncogenesis, including ZNF521, which may be candidates for diagnostic and prognostic biomarkers of cancer.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/genética , Animais , Carcinogênese/genética , Redes Reguladoras de Genes , Humanos , Fatores de Transcrição/genética
19.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445624

RESUMO

SBP-box is an important plant-specific transcription factor family and is involved in diverse biological processes. Here, we identified a total of 15 SBP-BOX genes in the important fruit crop sweet orange (Citrus sinensis) and characterized their gene structures, conserved domain and motif, chromosomal location, and cis-acting regulatory elements. SBP genes were classified into four subfamilies based on the amino acid sequence homology, and the classification is equally strongly supported by the gene and protein structures. Our analysis revealed that segmental duplication events were the main driving force in the evolution of CsSBP genes, and gene pairs might undergo extensive purifying selection. Further synteny analysis of the SBP members among sweet orange and other plant species provides valuable information for clarifying the CsSBP family evolutionary relationship. According to publicly available RNA-seq data and qRT-PCR analysis from various sweet orange tissues, CsSBP genes may be expressed in different tissues and developmental stages. Gene expression analysis showed variable expression profiles of CsSBP genes under various abiotic stresses, such as high and low-temperature, salt, and wound treatments, demonstrating the potential role of SBP members in sweet orange response to abiotic stress. Noticeably, all CsSBP genes were also downregulated in sweet orange upon the infection of an important fungal pathogen Diaporthe citri. Our results provide valuable information for exploring the role of SBP-Box in sweet orange.


Assuntos
Citrus sinensis/metabolismo , Regulação da Expressão Gênica de Plantas , Genoma de Planta , Família Multigênica , Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismo , Citrus sinensis/genética , Citrus sinensis/crescimento & desenvolvimento , Perfilação da Expressão Gênica , Filogenia , Proteínas de Plantas/genética , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/genética
20.
J Enzyme Inhib Med Chem ; 36(1): 1715-1731, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34425716

RESUMO

Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative, compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC50 values of 0.36 µM (MGC-803 cells), 0.70 µM (HCT-116 cells), 1.04 µM (PC-3 cells), and 0.81 µM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo. Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP.


Assuntos
Antineoplásicos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Quinazolinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Nus , Estrutura Molecular , Quinazolinas/síntese química , Transdução de Sinais , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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