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1.
Epigenetics ; 8(7): 703-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23804146

RESUMO

HIV-infected subjects on highly active antiretroviral therapy (HAART) are susceptible to comorbid microbial infections in the oral cavity. We observed that primary oral epithelial cells (POECs) isolated from HIV+ subjects on HAART grow more slowly and are less innate immune responsive to microbial challenge when compared with POECs from normal subjects. These aberrant cells also demonstrate epigenetic differences that include reduction in histone deacetylase 1 (HDAC-1) levels and reduced total DNA methyltransferase (DNMT) activity specific to enzymes DNMT1 and DNMT3A. The DNMT activity correlates well with global DNA methylation, indicating that aberrant DNMT activity in HIV+ (on HAART) POECs leads to an aberrantly methylated epithelial cell phenotype. Overall, our results lead us to hypothesize that, in patients with chronic HIV infection on HAART, epigenetic changes in key genes result in increased vulnerability to microbial infection in the oral cavity.


Assuntos
Terapia Antirretroviral de Alta Atividade , Epigênese Genética , Células Epiteliais/metabolismo , Soropositividade para HIV/genética , Soropositividade para HIV/virologia , Boca/patologia , Proliferação de Células , Separação Celular , Parede Celular/química , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/genética , Células Epiteliais/patologia , Células Epiteliais/virologia , Fusobacterium nucleatum/metabolismo , Soropositividade para HIV/tratamento farmacológico , Humanos , Boca/metabolismo , Boca/virologia
2.
Cell Metab ; 15(3): 311-23, 2012 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-22405069

RESUMO

Diurnal variation in nitrogen homeostasis is observed across phylogeny. But whether these are endogenous rhythms, and if so, molecular mechanisms that link nitrogen homeostasis to the circadian clock remain unknown. Here, we provide evidence that a clock-dependent peripheral oscillator, Krüppel-like factor 15 transcriptionally coordinates rhythmic expression of multiple enzymes involved in mammalian nitrogen homeostasis. In particular, Krüppel-like factor 15-deficient mice exhibit no discernable amino acid rhythm, and the rhythmicity of ammonia to urea detoxification is impaired. Of the external cues, feeding plays a dominant role in modulating Krüppel-like factor 15 rhythm and nitrogen homeostasis. Further, when all behavioral, environmental and dietary cues were controlled in humans, nitrogen homeostasis exhibited an endogenous circadian rhythmicity. Thus, in mammals, nitrogen homeostasis exhibits circadian rhythmicity, and is orchestrated by Krüppel-like factor 15.


Assuntos
Relógios Circadianos/fisiologia , Proteínas de Ligação a DNA/metabolismo , Nitrogênio/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Animais , Western Blotting , Linhagem Celular , Imunoprecipitação da Cromatina , Relógios Circadianos/genética , Proteínas de Ligação a DNA/genética , Homeostase/genética , Homeostase/fisiologia , Humanos , Fatores de Transcrição Kruppel-Like , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/genética , Adulto Jovem
3.
Nature ; 483(7387): 96-9, 2012 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-22367544

RESUMO

Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada's syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, krüppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis.


Assuntos
Arritmias Cardíacas/fisiopatologia , Ritmo Circadiano/fisiologia , Sistema de Condução Cardíaco/fisiologia , Animais , Arritmias Cardíacas/complicações , Arritmias Cardíacas/genética , Células Cultivadas , Ritmo Circadiano/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Morte Súbita Cardíaca/etiologia , Eletrocardiografia , Regulação da Expressão Gênica , Frequência Cardíaca/fisiologia , Ventrículos do Coração/citologia , Fatores de Transcrição Kruppel-Like , Proteínas Interatuantes com Canais de Kv/biossíntese , Proteínas Interatuantes com Canais de Kv/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Musculares/citologia , Regiões Promotoras Genéticas/genética , Ratos , Fatores de Tempo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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