Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21.513
Filtrar
1.
Gene ; 803: 145895, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34384862

RESUMO

The expression profile of early B-cell factor (Ebf) genes and loss of function experiments denote a crucial role for these genes during the late stage of skeletogenesis. However, little is known regarding the expression and function of these genes during the early stage of skeletogenesis. Therefore, this study aimed to detail the spatiotemporal expression pattern of cEbf1, in comparison to cEbf2 and cEbf3, in chick limb buds and investigate its function during chondrogenesis. cEbf1-3 were co-expressed in the distal mesenchyme from a very early stage and later in the outer perichondrium and the surrounding noncartilaginous mesenchymal cells. Ebf1 loss of function through injection of RCASBP virus-carrying Ebf1 dominant-negative form (ΔEbf1) into the wing buds resulted in shortened skeletal elements with a clear defect in the chondrocyte differentiation program. In RCASBP-ΔEbf1 injected wing, the chondrogenesis was initiated normally but hindered at the maturation stage. Subsequently, the chondrocytes failed to become mature or hypertrophic and the long bone diaphysis was not properly developed. The final phenotype included shorter, thicker, and fused long bones. These phenotypic changes were associated with downregulation of the early [Sox9 and collagen type II (Col2a1)] and the late [alkaline phosphatase (AP)] chondrocytes differentiation markers in the limb buds. These results conclude that cEbf1 could be involved in a molecular cascade that promotes the terminal stages of chondrogenesis in the long bone anlagen.


Assuntos
Botões de Extremidades/crescimento & desenvolvimento , Transativadores/genética , Transativadores/metabolismo , Animais , Embrião de Galinha , Condrogênese , Regulação da Expressão Gênica no Desenvolvimento , Botões de Extremidades/metabolismo , Fenótipo
2.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361001

RESUMO

Epidermal progenitor cells divide symmetrically and asymmetrically to form stratified epidermis and hair follicles during late embryonic development. Flightless I (Flii), an actin remodelling protein, is implicated in Wnt/ß-cat and integrin signalling pathways that govern cell division. This study investigated the effect of altering Flii on the divisional orientation of epidermal progenitor cells (EpSCs) in the basal layer during late murine embryonic development and early adolescence. The effect of altering Flii expression on asymmetric vs. symmetric division was assessed in vitro in adult human primary keratinocytes and in vivo at late embryonic development stages (E16, E17 and E19) as well as adolescence (P21 day-old) in mice with altered Flii expression (Flii knockdown: Flii+/-, wild type: WT, transgenic Flii overexpressing: FliiTg/Tg) using Western blot and immunohistochemistry. Flii+/- embryonic skin showed increased asymmetrical cell division of EpSCs with an increase in epidermal stratification and elevated talin, activated-Itgb1 and Par3 expression. FliiTg/Tg led to increased symmetrical cell division of EpSCs with increased cell proliferation rate, an elevated epidermal SOX9, Flap1 and ß-cat expression, a thinner epidermis, but increased hair follicle number and depth. Flii promotes symmetric division of epidermal progenitor cells during murine embryonic development.


Assuntos
Divisão Celular , Proteínas dos Microfilamentos/genética , Células-Tronco Embrionárias Murinas/metabolismo , Pele/metabolismo , Transativadores/genética , Animais , Células Cultivadas , Queratinócitos/citologia , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Fatores de Transcrição SOX9/metabolismo , Pele/embriologia , Transativadores/metabolismo , beta Catenina/metabolismo
3.
FASEB J ; 35(9): e21833, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34365659

RESUMO

Macrophages are the principal component of the innate immune system. They play very crucial and multifaceted roles in the pathogenesis of inflammatory vascular diseases. There is an increasing recognition that transcriptionally dynamic macrophages are the key players in the pathogenesis of inflammatory vascular diseases. In this context, the accumulation and aberrant activation of macrophages in the subendothelial layers govern atherosclerotic plaque development. Macrophage-mediated inflammation is an explicitly robust biological response that involves broad alterations in inflammatory gene expression. Thus, cell-intrinsic negative regulatory mechanisms must exist which can restrain inflammatory response in a spatiotemporal manner. In this study, we identified CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as one such cell-intrinsic negative regulator of inflammation. Our in vivo studies show that myeloid-CITED2-deficient mice on the Apoe-/- background have larger atherosclerotic lesions on both control and high-fat/high-cholesterol diets. Our integrated transcriptomics and gene set enrichment analyses studies show that CITED2 deficiency elevates STAT1 and interferon regulatory factor 1 (IRF1) regulated pro-inflammatory gene expression in macrophages. At the molecular level, our studies identify that CITED2 deficiency elevates IFNγ-induced STAT1 transcriptional activity and STAT1 enrichment on IRF1 promoter in macrophages. More importantly, siRNA-mediated knockdown of IRF1 completely reversed elevated pro-inflammatory target gene expression in CITED2-deficient macrophages. Collectively, our study findings demonstrate that CITED2 restrains the STAT1-IRF1 signaling axis in macrophages and limits the development of atherosclerotic plaques.


Assuntos
Aterosclerose/genética , Fator Regulador 1 de Interferon/genética , Proteínas Repressoras/genética , Fator de Transcrição STAT1/genética , Transdução de Sinais/genética , Transativadores/genética , Animais , Feminino , Inflamação/genética , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Células RAW 264.7 , Transcrição Genética/genética
4.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445673

RESUMO

The transcription factor p63, one of the p53 family members, plays an essential role in regulating maternal reproduction and genomic integrity as well as epidermal development. TP63 (human)/Trp63 (mouse) produces multiple isoforms: TAp63 and ΔNp63, which possess a different N-terminus depending on two different promoters, and p63a, p63b, p63g, p63δ, and p63ε as products of alternative splicing at the C-terminus. TAp63 expression turns on in the nuclei of primordial germ cells in females and is maintained mainly in the oocyte nuclei of immature follicles. It has been established that TAp63 is the genomic guardian in oocytes of the female ovaries and plays a central role in determining the oocyte fate upon oocyte damage. Lately, there is increasing evidence that TP63 mutations are connected with female infertility, including isolated premature ovarian insufficiency (POI) and syndromic POI. Here, we review the biological functions of p63 in females and discuss the consequences of p63 mutations, which result in infertility in human patients.


Assuntos
Fertilidade/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Processamento Alternativo/genética , Animais , Núcleo Celular/metabolismo , Feminino , Genes p53/genética , Humanos , Camundongos , Mutação/genética , Oócitos/metabolismo , Ovário/metabolismo , Insuficiência Ovariana Primária/metabolismo , Isoformas de Proteínas/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
5.
J Med Microbiol ; 70(8)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34338626

RESUMO

Introduction. Biofilm formation is a major virulence factor associated with Staphylococcus aureus infections. However, the influence of plasma proteins on biofilm formation of clinical isolates in vitro remains unclear.Hypotheses. We hypothesized that coating surfaces with plasma proteins might induce biofilm formation by S. aureus of different clonal lineages.Aim. To evaluate biofilm production by clinical S. aureus isolates of different clonal lineages isolated in Rio de Janeiro hospitals and investigated the presence of biofilm-associated genes.Methodology. This study assessed biofilm production of 60 S. aureus isolates in polystyrene microtitre plates with and without fibrinogen or fibronectin. The biochemical composition of the biofilm matrices was determined and the biofilm formation on fibrinogen-coated surfaces was also evaluated by confocal laser scanning microscopy. The presence of biofilm-related genes was detected by PCR, and the typing and functionality of agr operon was also evaluated.Results. Most of the isolates (45 %) were weak biofilm producers or non-producers. However, most of them presented a significant increase in biofilm production on plates covered with plasma proteins. There was no significant difference in biofilm formation between methicillin-resistant and -susceptible S. aureus isolates, or between different clonal lineages, except for ST30-IV (weak producers) and ST239-III (strong producers). The fnbB gene was associated with higher biofilm production.Conclusion. An increase in biofilm production in the presence of plasma proteins highlights the importance of investigating biofilm formation by S. aureus clinical isolates under different conditions since this virulence factor contributes to persistent infections and increased resistance to antimicrobials.


Assuntos
Biofilmes/crescimento & desenvolvimento , Fibrinogênio , Fibronectinas , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Staphylococcus aureus/patogenicidade , Adesinas Bacterianas/genética , Aderência Bacteriana/genética , Proteínas de Bactérias/genética , Genes Bacterianos , Genótipo , Humanos , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/fisiologia , Óperon , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificação , Staphylococcus aureus/fisiologia , Transativadores/genética
6.
Int J Mol Sci ; 22(15)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34361053

RESUMO

Leaf senescence is a genetically regulated developmental process that can be triggered by a variety of internal and external signals, including hormones and environmental stimuli. Among the senescence-associated genes controlling leaf senescence, the transcriptional factors (TFs) comprise a functional class that is highly active at the onset and during the progression of leaf senescence. The plant-specific NAC (NAM, ATAF, and CUC) TFs are essential for controlling leaf senescence. Several members of Arabidopsis AtNAC-SAGs are well characterized as players in elucidated regulatory networks. However, only a few soybean members of this class display well-known functions; knowledge about their regulatory circuits is still rudimentary. Here, we describe the expression profile of soybean GmNAC-SAGs upregulated by natural senescence and their functional correlation with putative AtNAC-SAGs orthologs. The mechanisms and the regulatory gene networks underlying GmNAC081- and GmNAC030-positive regulation in leaf senescence are discussed. Furthermore, new insights into the role of GmNAC065 as a negative senescence regulator are presented, demonstrating extraordinary functional conservation with the Arabidopsis counterpart. Finally, we describe a regulatory circuit which integrates a stress-induced cell death program with developmental leaf senescence via the NRP-NAC-VPE signaling module.


Assuntos
Senescência Celular , Redes Reguladoras de Genes , Folhas de Planta/fisiologia , Proteínas de Plantas/metabolismo , Soja/fisiologia , Estresse Fisiológico , Transativadores/metabolismo , Proteínas de Plantas/genética , Transativadores/genética
7.
FASEB J ; 35(8): e21790, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34320252

RESUMO

CXXC Zinc finger protein 1 (CFP1) is a multitasking protein playing essential roles during various developmental processes. Its ability to interact with several proteins contribute to several epigenetic events. Here, we review CFP1's functions and its impact on DNA methylation and the post-translational modification of histone proteins such as lysine acetylation and methylation. We will also discuss the potential role of CFP1 in carcinogenesis and the impact of the mutations identified in patients suffering from various cancers.


Assuntos
Epigênese Genética , Mutação , Neoplasias/metabolismo , Transativadores/metabolismo , Animais , Regulação Neoplásica da Expressão Gênica , Humanos , Transativadores/genética
8.
J Immunol ; 207(4): 1044-1054, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34330753

RESUMO

Eosinophils develop in the bone marrow from hematopoietic progenitors into mature cells capable of a plethora of immunomodulatory roles via the choreographed process of eosinophilopoiesis. However, the gene regulatory elements and transcription factors (TFs) orchestrating this process remain largely unknown. The potency and resulting diversity fundamental to an eosinophil's complex immunomodulatory functions and tissue specialization likely result from dynamic epigenetic regulation of the eosinophil genome, a dynamic eosinophil regulome. In this study, we applied a global approach using broad-range, next-generation sequencing to identify a repertoire of eosinophil-specific enhancers. We identified over 8200 active enhancers located within 1-20 kB of expressed eosinophil genes. TF binding motif analysis revealed PU.1 (Spi1) motif enrichment in eosinophil enhancers, and chromatin immunoprecipitation coupled with massively parallel sequencing confirmed PU.1 binding in likely enhancers of genes highly expressed in eosinophils. A substantial proportion (>25%) of these PU.1-bound enhancers were unique to murine, culture-derived eosinophils when compared among enhancers of highly expressed genes of three closely related myeloid cell subsets (macrophages, neutrophils, and immature granulocytes). Gene ontology analysis of eosinophil-specific, PU.1-bound enhancers revealed enrichment for genes involved in migration, proliferation, degranulation, and survival. Furthermore, eosinophil-specific superenhancers were enriched in genes whose homologs are associated with risk loci for eosinophilia and allergic diseases. Our collective data identify eosinophil-specific enhancers regulating key eosinophil genes through epigenetic mechanisms (H3K27 acetylation) and TF binding (PU.1).


Assuntos
Cromatina/genética , Eosinófilos/metabolismo , Epigênese Genética/genética , Ligação Proteica/genética , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Animais , Células Cultivadas , Camundongos , Camundongos Endogâmicos BALB C , Células Mieloides , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/genética
9.
Cell Death Dis ; 12(7): 659, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193827

RESUMO

Cellular stress can lead to several human disease pathologies due to aberrant cell death. The p53 family (tp53, tp63, and tp73) and downstream transcriptional apoptotic target genes (PUMA/BBC3 and NOXA/PMAIP1) have been implicated as mediators of stress signals. To evaluate the importance of key stress response components in vivo, we have generated zebrafish null alleles in puma, noxa, p53, p63, and p73. Utilizing these genetic mutants, we have deciphered that the apoptotic response to genotoxic stress requires p53 and puma, but not p63, p73, or noxa. We also identified a delayed secondary wave of genotoxic stress-induced apoptosis that is p53/puma independent. Contrary to genotoxic stress, ER stress-induced apoptosis requires p63 and puma, but not p53, p73, or noxa. Lastly, the oxidative stress-induced apoptotic response requires p63, and both noxa and puma. Our data also indicate that while the neural tube is poised for apoptosis due to genotoxic stress, the epidermis is poised for apoptosis due to ER and oxidative stress. These data indicate there are convergent as well as unique molecular pathways involved in the different stress responses. The commonality of puma in these stress pathways, and the lack of gross or tumorigenic phenotypes with puma loss suggest that a inhibitor of Puma may have therapeutic application. In addition, we have also generated a knockout of the negative regulator of p53, mdm2 to further evaluate the p53-induced apoptosis. Our data indicate that the p53 null allele completely rescues the mdm2 null lethality, while the puma null completely rescues the mdm2 null apoptosis but only partially rescues the phenotype. Indicating Puma is the key mediator of p53-dependent apoptosis. Interestingly the p53 homozygous null zebrafish develop tumors faster than the previously described p53 homozygous missense mutant zebrafish, suggesting the missense allele may be hypomorphic allele.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Dano ao DNA , Estresse do Retículo Endoplasmático , Estresse Oxidativo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proteínas Reguladoras de Apoptose/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica , Macrolídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosfoproteínas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais , Acetato de Tetradecanoilforbol/farmacologia , Tapsigargina/farmacologia , Fatores de Tempo , Transativadores/genética , Transcrição Genética , Proteína Supressora de Tumor p53/genética , Raios X , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
10.
Cell Death Dis ; 12(7): 683, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234118

RESUMO

Ribonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorretais/enzimologia , Inibidores Enzimáticos/farmacologia , Técnicas de Silenciamento de Genes , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Ribonucleosídeo Difosfato Redutase/metabolismo , Transativadores/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Tirosina Quinases/metabolismo , Ribonucleosídeo Difosfato Redutase/genética , Transdução de Sinais , Transativadores/genética , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Development ; 148(14)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34313318

RESUMO

Heterozygosity of ribosomal protein genes causes a variety of developmental abnormalities in humans, which are collectively known as ribosomopathies, yet the underlying mechanisms remain elusive. Here, we analyzed Drosophila Minute (M)/+ mutants, a group of mutants heterozygous for ribosomal protein genes that exhibit a characteristic thin-bristle phenotype. We found that, although M/+ flies develop essentially normal wings, simultaneous deletion of one copy of the Hippo pathway effector yki resulted in severe wing growth defects. These defects were caused by JNK-mediated cell death in the wing pouch via Eiger/TNF signaling. The JNK activation in M/+, yki/+ wing discs required the caspase Dronc, which is normally blocked by DIAP1. Notably, heterozygosity of yki reduced DIAP1 expression in the wing pouch, leading to elevation of Dronc activity. Dronc and JNK formed a positive-feedback loop that amplifies Dronc activation, leading to apoptosis. Our observations suggest a mechanism of robust tissue growth whereby tissues with reduced ribosomal protein prevent ectopic apoptosis via Yki activity.


Assuntos
Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Animais , Apoptose , Morte Celular , Regulação para Baixo , Drosophila/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Nucleares/genética , Transdução de Sinais , Transativadores/genética , Asas de Animais/anatomia & histologia , Asas de Animais/metabolismo
12.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204945

RESUMO

A lesser known but crucially important downstream effect of Rho family GTPases is the regulation of gene expression. This major role is mediated via the cytoskeleton, the organization of which dictates the nucleocytoplasmic shuttling of a set of transcription factors. Central among these is myocardin-related transcription factor (MRTF), which upon actin polymerization translocates to the nucleus and binds to its cognate partner, serum response factor (SRF). The MRTF/SRF complex then drives a large cohort of genes involved in cytoskeleton remodeling, contractility, extracellular matrix organization and many other processes. Accordingly, MRTF, activated by a variety of mechanical and chemical stimuli, affects a plethora of functions with physiological and pathological relevance. These include cell motility, development, metabolism and thus metastasis formation, inflammatory responses and-predominantly-organ fibrosis. The aim of this review is twofold: to provide an up-to-date summary about the basic biology and regulation of this versatile transcriptional coactivator; and to highlight its principal involvement in the pathobiology of kidney disease. Acting through both direct transcriptional and epigenetic mechanisms, MRTF plays a key (yet not fully appreciated) role in the induction of a profibrotic epithelial phenotype (PEP) as well as in fibroblast-myofibroblast transition, prime pathomechanisms in chronic kidney disease and renal fibrosis.


Assuntos
Nefropatias/genética , Complexos Multiproteicos/genética , Fator de Resposta Sérica/genética , Transativadores/genética , Movimento Celular/genética , Núcleo Celular/genética , Citoesqueleto/genética , Regulação da Expressão Gênica/genética , Humanos , Nefropatias/patologia , Regiões Promotoras Genéticas/genética
13.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209079

RESUMO

Although hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with TERT (telomerase reverse transcriptase) alterations in paired tumor and non-tumor tissues. Compared to those in non-tumors, tumoral integrations occurred less frequently but with higher read counts and were more preferentially observed in genic regions with significant enrichment of integration into promoters. In HBV-related tumors, TERT promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. TERT promoter mutation was observed only in tumors (24.2% (8/33)), but not in non-tumors. Only 3.00% (34/1133) of HBV integration sites were shared between tumors and non-tumors. Within the HBV genome, HBV breakpoints were distributed preferentially in the 3' end of HBx, with more tumoral integrations detected in the preS/S region. The major genes that were recurrently affected by HBV integration included TERT and MLL4 for tumors and FN1 for non-tumors. Functional enrichment analysis of tumoral genes with integrations showed enrichment of cancer-associated genes. The patterns and functions of HBV integration are distinct between tumors and non-tumors. Tumoral integration is often enriched into both human-virus regions with oncogenic regulatory function. The characteristic genomic features of HBV integration together with TERT alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis.


Assuntos
Carcinoma Hepatocelular/virologia , Vírus da Hepatite B/fisiologia , Hepatite B/genética , Neoplasias Hepáticas/virologia , Mutação , Telomerase/genética , Adulto , Idoso , Carcinoma Hepatocelular/genética , Estudos de Casos e Controles , DNA Viral/genética , Feminino , Fibronectinas/genética , Hepatite B/complicações , Histona-Lisina N-Metiltransferase/genética , Humanos , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Transativadores/genética , Proteínas Virais Reguladoras e Acessórias/genética , Integração Viral
14.
Medicine (Baltimore) ; 100(28): e26215, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260521

RESUMO

OBJECTIVE: To explore whether rs4784227 polymorphism of CASC16 is correlated with risk of breast cancer. METHODS: Relevant studies up to December 24, 2020 were searched in PubMed, Embase, Web of Science, CNKI, VIP, and WANFANG databases. Data were analyzed by using Stata 12.0. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and country-based subgroup analyses were conducted. Sensitivity analysis was conducted to assess the stability of the results. Publication bias was assessed by using the Egger regression asymmetry test and visualization of funnel plots. RESULTS: Seven case-control studies enrolling 4055 breast cancer cases and 4229 controls were included. rs4784227 was found significantly associated with increased risk of breast cancer in a dominant (OR = 1.301, 95% CI = 1.190-1.423, P < .001), a recessive (OR = 1.431, 95% CI = 1.216-1.685, P < .001), and an allele model (OR = 1.257, 95% CI = 1.172-1.348, P < .001), while an over-dominant model showed that rs4784227 was correlated with decreased breast cancer risk (OR = 0.852, 95% CI = 0.778-0.933, P = .001). CONCLUSION: The rs4784227 polymorphism of CASC16 gene is correlated with breast cancer susceptibility.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Neoplasias da Mama/genética , Transativadores/genética , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco
15.
Nat Commun ; 12(1): 4164, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230493

RESUMO

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the ß-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/ß-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/ß-catenin interaction.


Assuntos
GTP Fosfo-Hidrolases/metabolismo , Proteínas de Membrana/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fator 1 de Transcrição de Linfócitos T/metabolismo , Transativadores/metabolismo , beta Catenina/metabolismo , Animais , Transplante de Medula Óssea , Carcinogênese/genética , Modelos Animais de Doenças , Feminino , GTP Fosfo-Hidrolases/genética , Células HEK293 , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Oncogenes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogênicas/genética , Fator 1 de Transcrição de Linfócitos T/genética , Linfócitos T/metabolismo , Transativadores/genética , Transcriptoma , beta Catenina/genética
16.
Nucleic Acids Res ; 49(12): 6756-6770, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34139014

RESUMO

The ability to fine tune global gene expression in response to host environment is critical for the virulence of pathogenic bacteria. The host temperature is exploited by the bacteria as a cue for triggering virulence gene expression. However, little is known about the mechanism employed by Pseudomonas aeruginosa to response to host body temperature. CspA family proteins are RNA chaperones that modulate gene expression. Here we explored the functions of P. aeruginosa CspA family proteins and found that CspC (PA0456) controls the bacterial virulence. Combining transcriptomic analyses, RNA-immunoprecipitation and high-throughput sequencing (RIP-Seq), we demonstrated that CspC represses the type III secretion system (T3SS) by binding to the 5' untranslated region of the mRNA of exsA, which encodes the T3SS master regulatory protein. We further demonstrated that acetylation at K41 of the CspC reduces its affinity to nucleic acids. Shifting the culture temperature from 25°C to 37°C or infection of mouse lung increased the CspC acetylation, which derepressed the expression of the T3SS genes, resulting in elevated virulence. Overall, our results identified the regulatory targets of CspC and revealed a regulatory mechanism of the T3SS in response to temperature shift and host in vivo environment.


Assuntos
Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Proteínas de Choque Térmico/metabolismo , Pseudomonas aeruginosa/genética , Transativadores/genética , Sistemas de Secreção Tipo III/genética , Células A549 , Acetilação , Animais , Proteínas de Bactérias/biossíntese , Humanos , Camundongos , Pneumonia Bacteriana/microbiologia , Regiões Promotoras Genéticas , Biossíntese de Proteínas , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidade , Transativadores/biossíntese , Virulência
17.
Nat Commun ; 12(1): 3849, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158508

RESUMO

DNA-RNA hybrid structures have been detected at the vicinity of DNA double-strand breaks (DSBs) occurring within transcriptional active regions of the genome. The induction of DNA-RNA hybrids strongly affects the repair of these DSBs, but the nature of these structures and how they are formed remain poorly understood. Here we provide evidence that R loops, three-stranded structures containing DNA-RNA hybrids and the displaced single-stranded DNA (ssDNA) can form at sub-telomeric DSBs. These R loops are generated independently of DNA resection but are induced alongside two-stranded DNA-RNA hybrids that form on ssDNA generated by DNA resection. We further identified UPF1, an RNA/DNA helicase, as a crucial factor that drives the formation of these R loops and DNA-RNA hybrids to stimulate DNA resection, homologous recombination, microhomology-mediated end joining and DNA damage checkpoint activation. Our data show that R loops and DNA-RNA hybrids are actively generated at DSBs to facilitate DNA repair.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA , DNA/metabolismo , Estruturas R-Loop , RNA Helicases/metabolismo , Transativadores/metabolismo , Sequência de Bases , Linhagem Celular , Linhagem Celular Tumoral , DNA/química , DNA/genética , DNA de Cadeia Simples/química , DNA de Cadeia Simples/genética , DNA de Cadeia Simples/metabolismo , Células HCT116 , Humanos , Hibridização de Ácido Nucleico , RNA/genética , RNA/metabolismo , RNA Helicases/genética , Interferência de RNA , Telômero/genética , Telômero/metabolismo , Transativadores/genética
18.
Development ; 148(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34128986

RESUMO

The balance between stem cell potency and lineage specification entails the integration of both extrinsic and intrinsic cues, which ultimately influence gene expression through the activity of transcription factors. One example of this is provided by the Hippo signalling pathway, which plays a central role in regulating organ size during development. Hippo pathway activity is mediated by the transcriptional co-factors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which interact with TEA domain (TEAD) proteins to regulate gene expression. Although the roles of YAP and TAZ have been intensively studied, the roles played by TEAD proteins are less well understood. Recent studies have begun to address this, revealing that TEADs regulate the balance between progenitor self-renewal and differentiation throughout various stages of development. Furthermore, it is becoming apparent that TEAD proteins interact with other co-factors that influence stem cell biology. This Primer provides an overview of the role of TEAD proteins during development, focusing on their role in Hippo signalling as well as within other developmental, homeostatic and disease contexts.


Assuntos
Suscetibilidade a Doenças , Desenvolvimento Embrionário , Regulação da Expressão Gênica no Desenvolvimento , Família Multigênica , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Biomarcadores , Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Homeostase , Humanos , Terapia de Alvo Molecular , Especificidade de Órgãos , Regeneração , Especificidade da Espécie , Células-Tronco/citologia , Células-Tronco/metabolismo , Transativadores/genética , Transativadores/metabolismo , Vertebrados
19.
Nat Commun ; 12(1): 3965, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172724

RESUMO

Eukaryotic gene expression is constantly controlled by the translation-coupled nonsense-mediated mRNA decay (NMD) pathway. Aberrant translation termination leads to NMD activation, resulting in phosphorylation of the central NMD factor UPF1 and robust clearance of NMD targets via two seemingly independent and redundant mRNA degradation branches. Here, we uncover that the loss of the first SMG5-SMG7-dependent pathway also inactivates the second SMG6-dependent branch, indicating an unexpected functional connection between the final NMD steps. Transcriptome-wide analyses of SMG5-SMG7-depleted cells confirm exhaustive NMD inhibition resulting in massive transcriptomic alterations. Intriguingly, we find that the functionally underestimated SMG5 can substitute the role of SMG7 and individually activate NMD. Furthermore, the presence of either SMG5 or SMG7 is sufficient to support SMG6-mediated endonucleolysis of NMD targets. Our data support an improved model for NMD execution that features two-factor authentication involving UPF1 phosphorylation and SMG5-SMG7 recruitment to access SMG6 activity.


Assuntos
Proteínas de Transporte/metabolismo , Degradação do RNAm Mediada por Códon sem Sentido/fisiologia , Proteínas de Transporte/química , Proteínas de Transporte/genética , Linhagem Celular , Feminino , Técnicas de Inativação de Genes , Humanos , Fosforilação , RNA Helicases/genética , RNA Helicases/metabolismo , Telomerase/metabolismo , Transativadores/genética , Transativadores/metabolismo
20.
Nat Commun ; 12(1): 3388, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099676

RESUMO

Wearable smart electronic devices, such as smart watches, are generally equipped with green-light-emitting diodes, which are used for photoplethysmography to monitor a panoply of physical health parameters. Here, we present a traceless, green-light-operated, smart-watch-controlled mammalian gene switch (Glow Control), composed of an engineered membrane-tethered green-light-sensitive cobalamin-binding domain of Thermus thermophilus (TtCBD) CarH protein in combination with a synthetic cytosolic TtCBD-transactivator fusion protein, which manage translocation of TtCBD-transactivator into the nucleus to trigger expression of transgenes upon illumination. We show that Apple-Watch-programmed percutaneous remote control of implanted Glow-controlled engineered human cells can effectively treat experimental type-2 diabetes by producing and releasing human glucagon-like peptide-1 on demand. Directly interfacing wearable smart electronic devices with therapeutic gene expression will advance next-generation personalized therapies by linking biopharmaceutical interventions to the internet of things.


Assuntos
Proteínas de Bactérias/efeitos da radiação , Diabetes Mellitus Tipo 2/terapia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Optogenética/métodos , Transativadores/efeitos da radiação , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Engenharia Celular , Diabetes Mellitus Tipo 2/genética , Feminino , Engenharia Genética , Peptídeo 1 Semelhante ao Glucagon/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células HEK293 , Humanos , Luz , Masculino , Células-Tronco Mesenquimais , Camundongos , Camundongos Obesos , Optogenética/instrumentação , Fotopletismografia/instrumentação , Domínios Proteicos/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/efeitos da radiação , Thermus thermophilus/genética , Transativadores/genética , Transativadores/metabolismo , Transgenes , Dispositivos Eletrônicos Vestíveis
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...