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1.
Exp Suppl ; 111: 263-298, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588536

RESUMO

Congenital pituitary hormone deficiency is a disabling condition. It is part of a spectrum of disorders including craniofacial midline developmental defects ranging from holoprosencephaly through septo-optic dysplasia to combined and isolated pituitary hormone deficiency. The first genes discovered in the human disease were based on mouse models of dwarfism due to mutations in transcription factor genes. High-throughput DNA sequencing technologies enabled clinicians and researchers to find novel genetic causes of hypopituitarism for the more than three quarters of patients without a known genetic diagnosis to date. Transcription factor (TF) genes are at the forefront of the functional analysis of novel variants of unknown significance due to the relative ease in in vitro testing in a research lab. Genetic testing in hypopituitarism is of high importance to the individual and their family to predict phenotype composition, disease progression and to avoid life-threatening complications such as secondary adrenal insufficiency.This chapter aims to highlight our current understanding about (1) the contribution of TF genes to pituitary development (2) the diversity of inheritance and phenotype features in combined and select isolated pituitary hormone deficiency and (3) provide an initial assessment on how to approach variants of unknown significance in human hypopituitarism. Our better understanding on how transcription factor gene variants lead to hypopituitarism is a meaningful step to plan advanced therapies to specific genetic changes in the future.


Assuntos
Hipopituitarismo/genética , Hipófise/fisiopatologia , Fatores de Transcrição/genética , Animais , Holoprosencefalia , Humanos , Camundongos , Mutação
2.
Anticancer Res ; 39(10): 5437-5448, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570438

RESUMO

BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) is a key multi-step process which enables cancer cells to detach from the epithelial primary tumor mass and allows them to metastasize to distant organs. We immunohistochemically analyzed the expression of the transcription factors (TWIST-1, SLUG, ZEB1, ZEB2) and components of the extracellular matrix (laminin-5, fibronectin) which influence the EMT. MATERIALS AND METHODS: Primary human breast (MDA-MB-231), colon (HT29, HCT116), ovarian (SKOV3, OVCAR3) and head and neck squamous cell carcinoma cell lines (UTSCC2, UTSCC24A) grown as xenografts were immunohistochemically analyzed in vitro and in vivo. RESULTS: A high SLUG expression was observed in every cancer entity both in vitro and in vivo. ZEB1 and ZEB2 showed a high in vivo expression especially in SKOV3 and in in vitro grown MDA-MB-231 cells. CONCLUSION: SLUG expression showed the highest expression in all cancer entities investigated. Hence, it presumably represents the master regulator of EMT in these metastatic tumor entities.


Assuntos
Biomarcadores Tumorais/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Matriz Extracelular/metabolismo , Células HCT116 , Células HT29 , Humanos , Imuno-Histoquímica/métodos , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 993-995, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598943

RESUMO

OBJECTIVE: To explore the genetic etiology of a pedigree affected with tricho-rhino-phalangeal syndrome. METHODS: Next-generation sequencing (NGS) using a gene panel for hereditary osteopathies was carried out for the proband. Suspected mutation was validated in the proband and her parents by Sanger sequencing. RESULTS: A heterozygous frameshift variation c.1995dupA (p.Gly666Argfs*20) of the TRPS1 gene was detected in the proband but not in her parents. CONCLUSION: The novel c.1995dupA (p.Gly666Argfs*20) mutation of the TRPS1 gene probably underlies the disease in the proband.


Assuntos
Proteínas de Ligação a DNA/genética , Dedos/anormalidades , Mutação da Fase de Leitura , Doenças do Cabelo/genética , Síndrome de Langer-Giedion/genética , Nariz/anormalidades , Fatores de Transcrição/genética , Feminino , Humanos , Linhagem
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 1028-1030, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598953

RESUMO

OBJECTIVE: To carry out genetic testing for a family with two pregnancies affected with hydrops fetalis and dilated cardiomyopathy (DCM) of the fetus. METHODS: DNA was extracted from fetal tissue as well as peripheral blood samples from the couple. Single nucleotide polymorphism array (SNP array) and next-generation sequencing (NGS) were carried out to screen potential mutation. Suspected mutation was validated with PCR and Sanger sequencing. RESULTS: The manifestation of fetal echocardiography was consistent with DCM. No obvious abnormality was found by SNP array analysis. A hemizygous c.481G>A (p.G161R) mutation of the TAZ gene was detected in the male fetus by NGS and confirmed by Sanger sequencing. The mutation was inherited from his mother. CONCLUSION: Barth syndrome due to the c.481G>A mutation of the TAZ gene probably underlies the recurrent hydrops fetalis and fetal DCM in this family.


Assuntos
Cardiomiopatia Dilatada/genética , Hidropisia Fetal/genética , Fatores de Transcrição/genética , Síndrome de Barth/genética , Ecocardiografia , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Gravidez
5.
Int Heart J ; 60(5): 1113-1122, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31484864

RESUMO

Occurring in about 1% of all live births, congenital heart defects (CHDs) represent the most frequent type of developmental abnormality and account for remarkably increased infant morbidity and mortality. Aggregating studies demonstrate that genetic components have a key role in the occurrence of CHDs. Nevertheless, due to pronounced genetic heterogeneity, the genetic causes of CHDs remain unclear in most patients. In this research, 114 unrelated patients affected with CHDs and 218 unrelated individuals without CHDs served as controls were recruited. The coding regions and splicing donors/acceptors of the ISL1 gene, which codes for a transcription factor required for proper cardiovascular development, were screened for mutations by sequencing in all study participants. The functional characteristics of an identified ISL1 mutation were delineated with a dual-luciferase reporter assay system. As a result, a new heterozygous ISL1 mutation, NM_002202.2: c.225C>G; p. (Tyr75*), was discovered in an index patient with double outlet right ventricle and ventricular septal defect. Analysis of the proband's family unveiled that the mutation co-segregated with the CHD phenotype. The nonsense mutation was absent in the 436 control chromosomes. Biological analysis showed that the mutant ISL1 protein had no transcriptional activity. Furthermore, the mutation nullified the synergistic activation between ISL1 and TBX20, another CHD-associated transcription factor. This research for the first time links an ISL1 loss-of-function mutation to double outlet right ventricle in humans, which adds insight to the molecular pathogenesis underpinning CHDs, suggesting potential implications for timely personalized management of CHD patients.


Assuntos
Dupla Via de Saída do Ventrículo Direito/genética , Genes Reporter/genética , Predisposição Genética para Doença/epidemiologia , Proteínas com Homeodomínio LIM/genética , Mutação com Perda de Função/genética , Fatores de Transcrição/genética , Estudos de Casos e Controles , Causalidade , Pré-Escolar , China/epidemiologia , Dupla Via de Saída do Ventrículo Direito/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Heterozigoto , Hospitais Universitários , Humanos , Incidência , Lactente , Masculino , Mutação , Linhagem , Prognóstico , Estudos Retrospectivos , Medição de Risco
6.
J Agric Food Chem ; 67(37): 10513-10520, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31475823

RESUMO

Amino acids can stimulate milk fat synthesis, but the underlying molecular mechanism is still largely unknown. In this study, we studied the regulatory role and corresponding molecular mechanism of cAMP response element-binding protein-regulated transcription coactivator 2 (CRTC2) in amino acid-induced milk fat synthesis in mammary epithelial cells. We showed that leucine and methionine stimulated CRTC2 but not p-CRTC2(Ser171) expression and nuclear localization in cow mammary epithelial cells. Knockdown of CRTC2 decreased milk fat synthesis and sterol regulatory element binding protein 1c (SREBP-1c) expression and activation, whereas its overexpression had the opposite effects. Neither knockdown nor overexpression of CRTC2 affected ß-casein synthesis and phosphorylation of the machanistic target of rapamycin (mTOR), suggesting that CRTC2 only regulates milk fat synthesis. CRTC2 knockdown abolished the stimulation of leucine and methionine on SREBP-1c expression and activation. Knockdown or overexpression of CRTC2 did not affect the protein level of cAMP-response element-binding protein (CREB) and its phosphorylation but decreased or increased the binding of p-CREB to the promoter of SREBP-1c gene and its mRNA expression, respectively. Mutation of Ser171 of CRTC2 did not alter the stimulation of CRTC2 on SREBP-1c expression and activation, further suggesting that CRTC2 functions in the nucleus. mTOR inhibition by rapamycin totally blocked the stimulation of leucine and methionine on CRTC2 expression. The expression of CRTC2 was dramatically higher in the mouse mammary gland of lactation period, compared with that of the dry and puberty periods, whereas p-CRTC2(Ser171) was not changed, further supporting that CRTC2 is a key transcription coactivator for milk fat synthesis. These results uncover that CRTC2 is a key transcription coactivator of amino acid-stimulated mTOR-mediated milk fat synthesis in mammary epithelial cells.


Assuntos
Aminoácidos/metabolismo , Bovinos/metabolismo , Células Epiteliais/metabolismo , Gorduras/metabolismo , Glândulas Mamárias Animais/citologia , Leite/metabolismo , Fatores de Transcrição/metabolismo , Animais , Bovinos/genética , Feminino , Glândulas Mamárias Animais/metabolismo , Camundongos , Fosforilação , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética
7.
J Agric Food Chem ; 67(39): 10891-10903, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31505929

RESUMO

Jasmonates (JAs) play an important role in plant developmental processes and regulate the biosynthesis of various specialized metabolites, and transcription factors are crucial in mediating JA signaling to regulate these processes. Capsaicinoids (Caps) are intriguing specialized metabolites produced uniquely by Capsicum species that give their fruits a pungent flavor to defend against herbivory and pathogens. In this study, we identify a R2R3-MYB transcription factor CaMYB108 and demonstrate its roles in regulating the biosynthesis of Caps and stamen development. Transcriptional analysis indicated that CaMYB108 was preferentially expressed in the flower and fruit, while the subcellular localization of CaMYB108 was shown to be the nucleus. Virus-induced gene silencing of CaMYB108 led to the expression of capsaicinoid biosynthetic genes (CBGs), and the contents of Caps dramatically reduce. Moreover, the CaMYB108-silenced plants showed delayed anther dehiscence and reduced pollen viability. Transient overexpression of CaMYB108 caused the expression of CBGs to be upregulated, and the Caps content significantly increased. The results of dual-luciferase reporter assays showed that CaMYB108 targeted CBG promoters. In addition, the expression of CaMYB108 and CBGs was inducible by methyl jasmonate and was consistent with the increased content of Caps. Overall, our results indicate that CaMYB108 is involved in the regulation of Caps biosynthesis and stamen development.


Assuntos
Capsaicina/metabolismo , Capsicum/metabolismo , Ciclopentanos/metabolismo , Flores/crescimento & desenvolvimento , Oxilipinas/metabolismo , Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismo , Capsicum/genética , Capsicum/crescimento & desenvolvimento , Flores/genética , Flores/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Pólen/genética , Pólen/crescimento & desenvolvimento , Pólen/metabolismo , Regiões Promotoras Genéticas , Fatores de Transcrição/genética
8.
Acta Virol ; 63(3): 286-291, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507194

RESUMO

Schmallenberg virus (SBV), a neurotropic member of the genus Orthobunyavirus, infects ruminants and causes neurological lesions and fetal malformations including cerebellar hypoplasia, hydranencephaly, and porencephaly. The aim of this study is to establish intracerebral (i.c.) infection of SBV in newborn BALB/c mice and to investigate some of the transcription factors in brain. For this aim, brain samples of newborn BALB/c mice which were infected with SBV i.c. were analyzed by plaque titration and real-time RT-PCR for T-bet, Gata3, RoRγt, Foxp3 and Eomes mRNA levels. Study results showed that SBV can replicate in BALB/c mice brain and cause death of newborn mice with generation of infectious viral particles. Analyses of transcription factor mRNA levels indicated up-regulation of T-bet, Gata3, RoRγt, Foxp3 and down-regulation of Eomes. In this report, we introduce preliminary data of T cell transcription factors affected by SBV infection of BALB/c mice. Keywords: Eomes; Foxp3; Gata3; RoRγt; Schmallenberg virus; T-bet.


Assuntos
Encéfalo , Infecções por Bunyaviridae , Regulação da Expressão Gênica , Orthobunyavirus , Fatores de Transcrição , Animais , Animais Recém-Nascidos , Encéfalo/virologia , Infecções por Bunyaviridae/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ruminantes , Fatores de Transcrição/genética , Replicação Viral
9.
Zhonghua Zhong Liu Za Zhi ; 41(9): 667-674, 2019 Sep 23.
Artigo em Chinês | MEDLINE | ID: mdl-31550856

RESUMO

Objective: To investigate the effect of long-chain non-coding RNA Fez family zinc finger protein 1 antisense RNA1 (lncRNA FEZF1-AS1) on the biological function of hepatocellular carcinoma (HCC). Methods: SMMC771 and BEL-7402 cells were transfected with sh-FEZF1-AS1 and OE-FEZF1-AS1, respectively. The expression of lncRNA FEZF1-AS1 was detected by real-time quantitative PCR. Cell proliferation was detected by Cell Counting Kit-8 (CCK-8), and apoptosis was detected by flow cytometry. The effects of lncRNA FEZF1-AS1 on invasion and migration were detected by Transwell and wound healing assays. The expression levels of adhesion molecules were detected by Western blot. The effect of lncRNA FEZF1-AS1 on the in vivo growth was verified by nude mice xenograft experiments. Results: The silencing or ectopic expression of lncRNA FEZF1-AS1 inhibited or promoted the proliferation of hepatocellular carcinoma cells. CCK-8 assay showed that the proliferation abilities of SMMC7721 and BEL-7402 cells in sh-FEZF1-AS1 transfection group significantly decreased, achieving (35.43±4.06)% and (34.68±3.97)%, respectively, on the fifth day. There were significant differences between sh-FEZF1-AS1 group and sh-NC group [52.21±8.46)% and (53.76±7.64)%] (all P<0.05). In contrast, the proliferation ability of SMMC7721 and BEL-7402 cells transfected with OE-FEZF1-AS1 was significantly increased, achieving (83.49±6.92)% and (80.31±3.13)%, respectively, on the fifth day. There were significant differences between OE-FEZF1-AS1 and OE-NC group [53.03±8.84)% and (55.11±7.09)%] (all P<0.05). The subsequent flow cytometry results showed that cell apoptotic rates of SMMC7721 and BEL-7402 cells transfected with sh-FEZF1-AS1 were (13.02±1.38)% and (11.88±1.29)%, respectively, which were significantly higher than those in sh-NC groups [(5.57±1.46)% and (8.06±1.42)%, respectively, all P<0.05]. In contrast, the apoptotic rates of SMMC7721 and BEL-7402 cells transfected with OE-FEZF1-AS1 were (3.01±0.39)% and (3.22±0.43)%, which were significantly lower than those in OE-NC groups [(6.68±0.96)% and (6.63±0.45)%, all P<0.05]. In addition, knockdown or overexpression of lncRNA FEZF1-AS1 expression inhibited or enhanced the migration and invasion abilities as well as the levels of adhesion molecules in hepatocellular carcinoma cells. After 30 days of feeding under the same conditions, the tumor volumes of sh-FEZF1-AS1 and sh-NC SMMC7721 cells xenograft mice models were (0.26±0.03) cm(3) and (0.63±0.06) cm(3), respectively, showing significant difference (P<0.05). The tumor volumes of sh-FEZF1-AS1 and sh-NC BEL-7402 cells were (0.31±0.02) cm(3) and (0.72±0.08) cm(3), and the difference was statistically significant (P<0.05). Conclusion: lncRNA FEZF1-AS1 may strengthen the growth, migration and invasion of hepatocellular carcinoma cells.


Assuntos
Carcinoma Hepatocelular , Movimento Celular , Proliferação de Células , Neoplasias Hepáticas , RNA Longo não Codificante , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proteínas de Ligação a DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Proteínas do Tecido Nervoso , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição
10.
Chem Biol Interact ; 312: 108813, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494105

RESUMO

Rhabdomyosarcoma (RMS) is a pediatric tumor, which arises from muscle precursor cells. Recently, it has been demonstrated that Hippo Pathway (Hpo), a pathway that regulates several physiological and biological features, is involved in RMS tumorigenesis. For instance, an upregulation of the Hpo downstream effector Yes-Associated Protein 1 (YAP) leads to the development of embryonal rhabdomyosarcoma (eRMS) in murine activated muscle satellite cells. On the other hand, the YAP paralog transcriptional co-activator with PDZ-binding motif (TAZ) is overexpressed in alveolar rhabdomyosarcoma (aRMS) patients with poor survival. YAP and TAZ exhibit both cytoplasmic and nuclear functions. In the nucleus, YAP binds TEADs (TEA domain family members) factors and together they constitute a complex that is able either to activate the transcription of several genes such as MYC, Tbx5 and PAX8 or to maintain the stability of others like p73. Due to the key role of YAP and TAZ in cancer, the identification and/or development of new compounds able to block their activity might be an effective antineoplastic strategy. Verteporfin (VP) is a molecule able to stop the formation of YAP/TEAD complex in the nucleus. The aim of this study is to evaluate the action of VP on RMS cell lines. This work shows that VP has an anti-proliferative activity on all RMS cell lines analyzed. Depending on RMS cell lines, VP affects cell cycle differently. Moreover, VP is able to decrease YAP protein levels, and to induce the activation of apoptosis mechanism through the cleavage of PARP-1. In addition, Annexin V assay showed the activation of apoptosis and necrosis after VP treatment. In summary, the ability of VP to disrupt RMS cell proliferation could be a novel and valuable strategy to improve the therapeutic approaches in treating rhabdomyosarcoma.


Assuntos
Proliferação de Células/efeitos dos fármacos , Verteporfina/farmacologia , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/metabolismo , Rabdomiossarcoma Embrionário/patologia , Fatores de Transcrição/metabolismo
11.
Z Rheumatol ; 78(8): 775-788, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31535201

RESUMO

Glucocorticoids (GC) have been proven drug substances in rheumatology for more than 70 years. They act very rapidly in high doses through membrane stabilizing effects. Genomic therapeutic effects of GC even in very low doses are mainly due to inhibition of the functions of the transcription factor nuclear factor kappa B (NFkB), which promotes the synthesis of proinflammatory mediators, adhesion molecules and other regulatory proteins. Indications for the use of GC in high doses in rheumatology are always given when a life-threatening, dangerous or treatment-resistant situation is involved. Lower doses of GC, usually administered orally, are particularly used in rheumatoid arthritis, vasculitis and collagenosis. In clinical practice the general principle is to use the smallest possible effective dose of GC for the shortest possible time in order to achieve the therapeutic effect of GC without running the risk of unacceptably severe side effects.


Assuntos
Glucocorticoides/uso terapêutico , Doenças Reumáticas , Reumatologia , Artrite Reumatoide , Relação Dose-Resposta a Droga , Glucocorticoides/efeitos adversos , Humanos , Doenças Reumáticas/tratamento farmacológico , Febre Reumática , Fatores de Transcrição
12.
Genes Dev ; 33(17-18): 1117-1135, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481536

RESUMO

T-cell development in mammals is a model for lineage choice and differentiation from multipotent stem cells. Although T-cell fate choice is promoted by signaling in the thymus through one dominant pathway, the Notch pathway, it entails a complex set of gene regulatory network and chromatin state changes even before the cells begin to express their signature feature, the clonal-specific T-cell receptors (TCRs) for antigen. This review distinguishes three developmental modules for T-cell development, which correspond to cell type specification, TCR expression and selection, and the assignment of cells to different effector types. The first is based on transcriptional regulatory network events, the second is dominated by somatic gene rearrangement and mutation and cell selection, and the third corresponds to establishing a poised state of latent regulator priming through an unknown mechanism. Interestingly, in different lineages, the third module can be deployed at variable times relative to the completion of the first two modules. This review focuses on the gene regulatory network and chromatin-based kinetic constraints that determine activities of transcription factors TCF1, GATA3, PU.1, Bcl11b, Runx1, and E proteins in the primary establishment of T-cell identity.


Assuntos
Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Linfócitos T/citologia , Animais , Diferenciação Celular/genética , Linhagem da Célula , Cromatina/metabolismo , Redes Reguladoras de Genes , Hematopoese , Linfócitos T/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31559011

RESUMO

It is well established that mitochondria play a critical role in the metabolic and physiological adaptation of skeletal muscle to enhanced contractile activity. Several redox-sensitive signaling pathways such as PGC-1α, AMPK, IGF/Akt/mTOR, SIRT, NFκB, and FoxO are involved with extensive crosstalk to regulate vital cellular functions such as mitochondrial biogenesis, mitochondrial fusion and fission dynamics, autophagy/mitophagy, and apoptosis under altered demand and stress. However, when muscles cease contraction, such as during immobilization and denervation, mitochondria undergo a series of detrimental changes characterized by downregulation of PGC-1α and antioxidant defense, increased ROS generation, activated FoxO, NFκB, and inflammation, enhanced ubiquitination, and finally mitophagy and apoptotic cascades. The phenotypic outcome of the discord of mitochondrial homeostasis is elevated proteolysis and muscle atrophy. The demonstration that PGC-1α overexpression via transgene or in vivo DNA transfection can restore mitochondrial homeostasis and reverse myocyte atrophy supports the "mitostasis theory of muscle atrophy".


Assuntos
Degradação Mitocondrial , Atrofia Muscular , Transtornos Musculares Atróficos , Fatores de Transcrição , Humanos , Mitocôndrias , Atrofia Muscular/fisiopatologia
14.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31559012

RESUMO

Scientific and technological advances of the past decade have shed light on the mechanisms underlying cell fate acquisition, including its transcriptional and epigenetic regulation during embryonic development. This knowledge has enabled us to purposefully engineer cell fates in vitro by manipulating expression levels of lineage-instructing transcription factors. Here, we review the state of the art in the cell programming field with a focus on the derivation of neural cells. We reflect on what we know about the mechanisms underlying fate changes in general and on the degree of epigenetic remodeling conveyed by the distinct reprogramming and direct conversion strategies available. Moreover, we discuss the implications of residual epigenetic memory for biomedical applications such as disease modeling and neuroregeneration. Finally, we cover recent developments approaching cell fate conversion in the living brain and define questions which need to be addressed before cell programming can become an integral part of translational medicine.


Assuntos
Reprogramação Celular , Epigênese Genética , Diferenciação Celular , Desenvolvimento Embrionário , Fatores de Transcrição
15.
Zhonghua Bing Li Xue Za Zhi ; 48(8): 590-595, 2019 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-31422588

RESUMO

Objective: To investigate the expression of SMARCA4 (BRG1) and SMARCB1 (INI-1) protein in endometrial dedifferentiated carcinoma (DDC) and undifferentiated carcinoma (UDC), and their correlation with clinicopathologic features. Methods: Clinicopathological information was gathered for 26 cases of DDC and UDC and consulting hospitals from January, 2006 to December, 2018 in Fudan University Shanghai Cancer Center, including 10 cases of DDC and 16 cases of UDC. Morphologic features and diagnosis were reviewed by two pathologists. Immunohistochemistry for expression of BRG1 and INI1 protein was performed. The correlations with clinicopathologic features were analyzed. Results: BRG1 and INI1 loss were present in 14 of 26 cases of DDC/UDC, including 12 BRG1-deficient cases and 2 INI1-deficient cases, respectively. Six cases demonstrated variable amounts of rhabdoid cells in 14 BRG1/INI1-deficient cases, and only 1 case showed rhabdoid cells in the 12 intact expression cases. However, there was no significantly statistical difference (P=0.060). Age, invasive depth, lymph node status and FIGO stage were not associated with the expression of the BRG1 and INI1 (P=0.437, P=0.672, P=0.242, P=0.348). Remarkably, the BGR1/INI1-deficient patients had worse survival than those with intact expression (4.7 vs. 22.9, P=0.033). Conclusion: BRG1/INI1-deficient is observed in approximately half of DDC and UDC. Identification of these tumors is clinically relevant due to their more aggressive behavior and poor prognosis. Hence, BRG1 and INI1 immunohistochemical stains should be performed for DDC and UDC in order to help the pathologists to distinguish these tumors from other carcinomas, and to predict the clinical prognosis.


Assuntos
DNA Helicases/metabolismo , Neoplasias do Endométrio , Proteínas Nucleares/metabolismo , Proteína SMARCB1/metabolismo , Fatores de Transcrição/metabolismo , Biomarcadores Tumorais , China , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , Imuno-Histoquímica
16.
Adv Exp Med Biol ; 1173: 21-32, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456203

RESUMO

Iron is an essential trace element in the human body, but excess iron is toxic as it contributes to oxidative damage. To keep iron concentration within the optimal physiologic range, iron metabolism at the cellular level and the whole systemic level are tightly regulated. Balance of iron homeostasis depends on the expression levels and activities of iron carriers, iron transporters, and iron regulatory and storage proteins. Divalent metal transporter 1 (DMT1) at the apical membrane of intestinal enterocyte brings in non-heme iron from the diet, whereas ferroportin 1 (FPN1) at the basal membrane exports iron into the circulation. Plasma transferrin (Tf) then carries iron to various tissues and cells. After binding to transferrin receptor 1 (TfR1), the complex is endocytosed into the cell, where iron enters the cytoplasm via DMT1 on the endosomal membrane. Free iron is either utilized in metabolic processes, such as synthesis of hemoglobin and Fe-S cluster, or sequestered in the cytosolic ferritin, serving as a cellular iron store. Excess iron can be exported from the cell via FPN1. The liver-derived peptide hepcidin plays a major regulatory role in controlling FPN1 level in the enterocyte, and thus controls the whole-body iron absorption. Inside the cells, iron regulatory proteins (IRPs) modulate the expressions of DMT1, TfR1, ferritin, and FPN1 via binding to the iron-responsive element (IRE) in their mRNAs. Both the release of hepcidin and the IRP-IRE interaction are coordinated with the fluctuation of the cellular iron level. Therefore, an adequate and steady iron supplement is warranted for the utilization of cells around the body. Investigations on the molecular mechanisms of cellular iron metabolism and regulation could advance the fields of iron physiology and pathophysiology.


Assuntos
Ferro/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Enterócitos/metabolismo , Ferritinas/metabolismo , Homeostase , Humanos , Sobrecarga de Ferro , Receptores da Transferrina/metabolismo , Fatores de Transcrição/metabolismo , Transferrina/metabolismo
17.
BMC Plant Biol ; 19(1): 342, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387526

RESUMO

BACKGROUND: GRAS are plant-specific transcription factors that play important roles in plant growth and development. Although the GRAS gene family has been studied in many plants, there has been little research on the GRAS genes of Tartary buckwheat (Fagopyrum tataricum), which is an important crop rich in rutin. The recently published whole genome sequence of Tartary buckwheat allows us to study the characteristics and expression patterns of the GRAS gene family in Tartary buckwheat at the genome-wide level. RESULTS: In this study, 47 GRAS genes of Tartary buckwheat were identified and divided into 10 subfamilies: LISCL, HAM, DELLA, SCR, PAT1, SCL4/7, LAS, SHR, SCL3, and DLT. FtGRAS genes were unevenly distributed on 8 chromosomes, and members of the same subfamily contained similar gene structures and motif compositions. Some FtGRAS genes may have been produced by gene duplications; tandem duplication contributed more to the expansion of the GRAS gene family in Tartary buckwheat. Real-time PCR showed that the transcription levels of FtGRAS were significantly different in different tissues and fruit development stages, implying that FtGRAS might have different functions. Furthermore, an increase in fruit weight was induced by exogenous paclobutrazol, and the transcription level of the DELLA subfamily member FtGRAS22 was significantly upregulated during the whole fruit development stage. Therefore, FtGRAS22 may be a potential target for molecular breeding or genetic editing. CONCLUSIONS: Collectively, this systematic analysis lays a foundation for further study of the functional characteristics of GRAS genes and for the improvement of Tartary buckwheat crops.


Assuntos
Fagopyrum/genética , Proteínas de Plantas/fisiologia , Fatores de Transcrição/fisiologia , Fagopyrum/crescimento & desenvolvimento , Fagopyrum/metabolismo , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Genoma de Planta , Família Multigênica , Filogenia , Desenvolvimento Vegetal/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Sintenia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Triazóis/farmacologia
18.
BMC Plant Biol ; 19(1): 344, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31390980

RESUMO

BACKGROUND: In the study, the trihelix family, also referred to as GT factors, is one of the transcription factor families. Trihelix genes play roles in the light response, seed maturation, leaf development, abiotic and biological stress and other biological activities. However, the trihelix family in tartary buckwheat (Fagopyrum tataricum), an important usable medicinal crop, has not yet been thoroughly studied. The genome of tartary buckwheat has recently been reported and provides a theoretical basis for our research on the characteristics and expression of trihelix genes in tartary buckwheat based at the whole level. RESULTS: In the present study, a total of 31 FtTH genes were identified based on the buckwheat genome. They were named from FtTH1 to FtTH31 and grouped into 5 groups (GT-1, GT-2, SH4, GTγ and SIP1). FtTH genes are not evenly distributed on the chromosomes, and we found segmental duplication events of FtTH genes on tartary buckwheat chromosomes. According to the results of gene and motif composition, FtTH located in the same group contained analogous intron/exon organizations and motif organizations. qRT-PCR showed that FtTH family members have multiple expression patterns in stems, roots, leaves, fruits, and flowers and during fruit development. CONCLUSIONS: Through our study, we identified 31 FtTH genes in tartary buckwheat and synthetically further analyzed the evolution and expression pattern of FtTH proteins. The structure and motif organizations of most genes are conserved in each subfamily, suggesting that they may be functionally conserved. The FtTH characteristics of the gene expression patterns indicate functional diversity in the time and space in the tartary buckwheat life process. Based on the discussion and analysis of FtTH gene function, we screened some genes closely related to the growth and development of tartary buckwheat. This will help us to further study the function of FtTH genes through experimental exploration in tartary buckwheat growth and improve the fruit of tartary buckwheat.


Assuntos
Fagopyrum/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismo , Mapeamento Cromossômico , Evolução Molecular , Fagopyrum/metabolismo , Duplicação Gênica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Genoma de Planta , Filogenia , Proteínas de Plantas/genética , Fatores de Transcrição/genética
19.
BMC Plant Biol ; 19(1): 352, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412781

RESUMO

BACKGROUND: Rice plants show yellowing, stunting, withering, reduced tillering and utimately low productivity in susceptible varieties under low temperature stress. Comparative transcriptome analysis was performed to identify novel transcripts, gain new insights into different gene expression and pathways involved in cold tolerance in rice. RESULTS: Comparative transcriptome analyses of 5 treatments based on chilling stress exposure revealed more down regulated genes in susceptible and higher up regulated genes in tolerant genotypes. A total of 13930 and 10599 differentially expressed genes (DEGs) were detected in cold susceptible variety (CSV) and cold tolerant variety (CTV), respectively. A continuous increase in DEGs at 6, 12, 24 and 48 h exposure of cold stress was detected in both the genotypes. Gene ontology (GO) analysis revealed 18 CSV and 28 CTV term significantly involved in molecular function, cellular component and biological process. GO classification showed a significant role of transcription regulation, oxygen, lipid binding, catalytic and hydrolase activity for tolerance response. Absence of photosynthesis related genes, storage products like starch and synthesis of other classes of molecules like fatty acids and terpenes during the stress were noticed in susceptible genotype. However, biological regulations, generation of precursor metabolites, signal transduction, photosynthesis, regulation of cellular process, energy and carbohydrate metabolism were seen in tolerant genotype during the stress. KEGG pathway annotation revealed more number of genes regulating different pathways resulting in more tolerant. During early response phase, 24 and 11 DEGs were enriched in CTV and CSV, respectively in energy metabolism pathways. Among the 1583 DEG transcription factors (TF) genes, 69 WRKY, 46 bZIP, 41 NAC, 40 ERF, 31/14 MYB/MYB-related, 22 bHLH, 17 Nin-like 7 HSF and 4C3H were involved during early response phase. Late response phase showed 30 bHLH, 65 NAC, 30 ERF, 26/20 MYB/MYB-related, 11 C3H, 12 HSF, 86 Nin-like, 41 AP2/ERF, 55 bZIP and 98 WRKY members TF genes. The recovery phase included 18 bHLH, 50 NAC, 31 ERF, 24/13 MYB/MYB-related, 4 C3H, 4 HSF, 14 Nin-like, 31 bZIP and 114 WRKY TF genes. CONCLUSIONS: Transcriptome analysis of contrasting genotypes for cold tolerance detected the genes, pathways and transcription factors involved in the stress tolerance.


Assuntos
Resposta ao Choque Frio/genética , Oryza/genética , Proteínas de Plantas/fisiologia , Fatores de Transcrição/fisiologia , Metabolismo Energético , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genótipo , Oryza/metabolismo , Oryza/fisiologia , Fotossíntese , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
20.
Sheng Wu Gong Cheng Xue Bao ; 35(8): 1500-1510, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31441621

RESUMO

MarR family transcription regulators are ubiquitous among bacteria and archaea. They extensively control multiple cellular processes and elaborately regulate the expression of genes involved in virulence, stress response and antibiotics at translational level. In Xanthomonas campestris pv. campestris, insertional inactivation of MarR family transcription regulator HpaR (XC2827) resulted in significantly decrease in virulence and increase in the production of the extracellular proteases. Here, we reported that the genome of Xcc 8004 encodes nine MarR family transcription regulators. The MarR family transcription regulators, HpaR (XC2827) and XC0449, were heterologous expressed and purified. In vitro MST and Pull-down assay confirmed the physical interaction between HpaR and XC0449. Phenotypical assay determined that deletion of XC0449 resulted in substantial virulence attenuation. In vitro EMSA, in vivo qRT-PCR and GUS activity assay identified that HpaR and XC0449 coordinately act as the transcriptional activator to regulate the expression of the virulence-associated gene XC0705, and eventually control the bacterial virulence and the production of extracellular proteases.


Assuntos
Xanthomonas campestris , Proteínas de Bactérias , Regulação Bacteriana da Expressão Gênica , Fatores de Transcrição , Virulência
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