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1.
FASEB J ; 35(9): e21814, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34369624

RESUMO

Alteration in glucose homeostasis during cancer metabolism is an important phenomenon. Though several important transcription factors have been well studied in the context of the regulation of metabolic gene expression, the role of epigenetic readers in this regard remains still elusive. Epigenetic reader protein transcription factor 19 (TCF19) has been recently identified as a novel glucose and insulin-responsive factor that modulates histone posttranslational modifications to regulate glucose homeostasis in hepatocytes. Here we report that TCF19 interacts with a non-histone, well-known tumor suppressor protein 53 (p53) and co-regulates a wide array of metabolic genes. Among these, the p53-responsive carbohydrate metabolic genes Tp53-induced glycolysis and apoptosis regulator (TIGAR) and Cytochrome C Oxidase assembly protein 2 (SCO2), which are the key regulators of glycolysis and oxidative phosphorylation respectively, are under direct regulation of TCF19. Remarkably, TCF19 can form different transcription activation/repression complexes which show substantial overlap with that of p53, depending on glucose-mediated variant stress situations as obtained from IP/MS studies. Interestingly, we observed that TCF19/p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short-term high glucose or prolonged high glucose conditions. TCF19 or p53 knockdown significantly altered the cellular lactate production and led to increased extracellular acidification rate. Similarly, OCR and cellular ATP production were reduced and mitochondrial membrane potential was compromised upon depletion of TCF19 or p53. Subsequently, through RNA-Seq analysis from patients with hepatocellular carcinoma, we observed that TCF19/p53-mediated metabolic regulation is fundamental for sustenance of cancer cells. Together the study proposes that TCF19/p53 complexes can regulate metabolic gene expression programs responsible for mitochondrial energy homeostasis and stress adaptation.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Mitocôndrias/genética , Chaperonas Moleculares/genética , Monoéster Fosfórico Hidrolases/genética , Fatores de Transcrição/genética , Transcrição Genética/genética , Proteína Supressora de Tumor p53/genética , Adaptação Biológica/genética , Apoptose/genética , Linhagem Celular Tumoral , Metabolismo Energético/genética , Glucose/genética , Células Hep G2 , Homeostase/genética , Humanos , Potencial da Membrana Mitocondrial/genética , Estresse Fisiológico/genética , Ativação Transcricional/genética
2.
Adv Clin Chem ; 95: 105-147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32122521

RESUMO

Long noncoding RNAs (lncRNAs) have recently gained considerable attention as key players in biological regulation; however, the mechanisms by which lncRNAs govern various disease processes remain mysterious and are just beginning to be understood. The ease of next-generation sequencing technologies has led to an explosion of genomic information, especially for the lncRNA class of noncoding RNAs. LncRNAs exhibit the characteristics of mRNAs, such as polyadenylation, 5' methyl capping, RNA polymerase II-dependent transcription, and splicing. These transcripts comprise more than 200 nucleotides (nt) and are not translated into proteins. Directed interrogation of annotated lncRNAs from RNA-Seq datasets has revealed dramatic differences in their expression, largely driven by alterations in transcription, the cell cycle, and RNA metabolism. The fact that lncRNAs are expressed cell- and tissue-specifically makes them excellent biomarkers for ongoing biological events. Notably, lncRNAs are differentially expressed in several cancers and show a distinct association with clinical outcomes. Novel methods and strategies are being developed to study lncRNA function and will provide researchers with the tools and opportunities to develop lncRNA-based therapeutics for cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , RNA Longo não Codificante/antagonistas & inibidores , Animais , Humanos , Neoplasias/genética , Neoplasias/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
3.
Biol Reprod ; 102(2): 327-338, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31511857

RESUMO

The ovarian hormones estrogen and progesterone orchestrate the transcriptional programs required to direct functions of the uterus for initiation and maintenance of pregnancy. Estrogen, acting via estrogen receptor alpha, regulates gene expression by activating and repressing distinct genes involved in signaling pathways that regulate cellular and physiological responses including cell division, water influx, and immune cell recruitment. Historically, these transcriptional responses have been postulated to reflect a biphasic physiological response. In this study, we explored the transcriptional responses of the ovariectomized mouse uterus to 17ß-estradiol (E2) by RNA-seq to obtain global expression profiles of protein-coding transcripts (mRNAs) and long noncoding RNAs (lncRNAs) following 0.5, 1, 2, and 6 hours of treatment. The E2-regulated mRNA and lncRNA expression profiles in the mouse uterus indicate an association between lncRNAs and mRNAs that regulate E2-driven pathways and reproductive phenotypes in the mouse. The transient E2-regulated transcriptome is reflected in the time-dependent shifting of biological processes regulated in the uterus in response to E2. Moreover, high expression of some conserved lncRNAs that are E2 regulated in the mouse uterus are predictive of low overall survival in endometrial carcinoma patients (e.g., H19, KCNQ1OT1, MIR17HG, and FTX). Collectively, this study (1) describes a genomic approach for identifying E2-regulated lncRNAs that may serve critical function in the uterus and (2) provides new insights into our understanding of the regulation of hormone-regulated transcriptional responses with implications in pregnancy and endometrial pathologies.


Assuntos
Estradiol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Transcriptoma/efeitos dos fármacos , Útero/efeitos dos fármacos , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Bases de Dados Genéticas , Feminino , Ontologia Genética , Neoplasias dos Genitais Femininos/genética , Neoplasias dos Genitais Femininos/metabolismo , Neoplasias dos Genitais Femininos/mortalidade , Humanos , Camundongos , Ovariectomia , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Taxa de Sobrevida , Útero/metabolismo
4.
PLoS One ; 13(9): e0203147, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30256791

RESUMO

The role of DNA methylation patterns in complex phenotypes remains unclear. To explore this question, we adapted our methods for rare variant analysis to characterize genome-wide murine DNA hybridization array to investigate methylation at CpG islands, shores, and regulatory elements. We have applied this platform to compare age and tissue- specific methylation differences in the brain and spleen of young and aged mice. As expected from prior studies, there are clear global differences in organ-specific, but not age-specific, methylation due mostly to changes at repetitive elements. Surprisingly, out of 200,000 loci there were only 946 differentially methylated cytosines (DMCs) between young and old samples (529 hypermethylated, 417 hypomethylated in aged mice) compared to thousands of tissue-specific DMCs. Hypermethylated loci were clustered around the promoter region of Sfi1, exon 2 of Slc11a2, Drg1, Esr1 and Foxa2 transcription factor binding sites. In particular, there were 75 hypermethylated Foxa2 binding sites across a 2.7 Mb region of chromosome 11. Hypomethylated loci were clustered around Mid1, Isoc2b and genome-wide loci with binding sites for Foxa2 and Esr1, which are known to play important roles in development and aging. These data suggest discreet tissue-independent methylation changes associated with aging processes such as cell division (Sfi1, Mid1), energy production (Drg1, Isoc2b) and cell death (Foxa2, Esr1).


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Metilação de DNA , Receptor alfa de Estrogênio/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Baço/metabolismo , Envelhecimento/genética , Animais , Sítios de Ligação , Biologia Computacional , Ilhas de CpG , Receptor alfa de Estrogênio/genética , Loci Gênicos , Fator 3-beta Nuclear de Hepatócito/genética , Camundongos Endogâmicos C57BL
5.
BMC Geriatr ; 16: 80, 2016 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-27060904

RESUMO

BACKGROUND: The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes. METHODS: We performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually or as a group across an entire gene for association to aging phenotypes using family based tests. RESULTS: We found significant associations to three genes and nine single variants. Most notably, we found a novel variant significantly associated with exceptional survival in the 3' UTR OBFC1 in 13 individuals from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation that was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL). CONCLUSIONS: Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants.


Assuntos
Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Longevidade/genética , Linhagem , Fenótipo , Idoso , Feminino , Testes Genéticos , Variação Genética/genética , Humanos , Masculino
6.
J Parasitol ; 95(2): 461-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18788881

RESUMO

Chagas disease, caused by Trypanosoma cruzi, is a widespread infection in Latin America. Currently, only 2 partially effective and highly toxic drugs, i.e., benznidazole and nifurtimox, are available for the treatment of this disease, and several efforts are underway in the search for better chemotherapeutic agents. Here, we have determined the trypanocidal activity of 2,3-diphenyl-1 ,4-naphthoquinone (DPNQ), a novel quinone derivative. In vitro, DPNQ was highly cytotoxic at a low, micromolar concentration (LD50 = 2.5 microM) against epimastigote, cell-derived trypomastigote, and intracellular amastigote forms of T. cruzi, but not against mammalian cells (LD50 = 130 microM). In vivo studies on the murine model of Chagas disease revealed that DPNQ-treated animals (3 doses of 10 mg/kg/day) showed a significant delay in parasitemia peak and higher (up to 60%) survival rate 70 days post-infection, when compared with the control group (infected, untreated). We also observed a 2-fold decrease in parasitemia between the control group (infected, untreated) and the treated group (infected, treated). No apparent drug toxicity effects were noticed in the control group (uninfected, treated). In addition, we determined that DPNQ is the first competitive inhibitor of T. cruzi lipoamide dehydrogenase (TcLipDH) thus far described. Our results indicate that DPNQ is a promising chemotherapeutic agent against T. cruzi.


Assuntos
Doença de Chagas/tratamento farmacológico , Naftoquinonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Doença de Chagas/parasitologia , Di-Hidrolipoamida Desidrogenase/antagonistas & inibidores , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Dose Letal Mediana , Camundongos , Camundongos Endogâmicos C3H , Naftoquinonas/química , Naftoquinonas/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/crescimento & desenvolvimento
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