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1.
Semin Cell Dev Biol ; 127: 121-132, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34426067

RESUMO

Inherited epigenetic information has been observed to regulate a variety of complex organismal phenotypes across diverse taxa of life. This continually expanding body of literature suggests that epigenetic inheritance plays a significant, and potentially fundamental, role in inheritance. Despite the important role these types of effects play in biology, the molecular mediators of this non-genetic transmission of information are just now beginning to be deciphered. Here we provide an intellectual framework for interpreting these findings and how they can interact with each other. We also define the different types of mechanisms that have been found to mediate epigenetic inheritance and to regulate whether epigenetic information persists for one or many generations. The field of epigenetic inheritance is entering an exciting phase, in which we are beginning to understand the mechanisms by which non-genetic information is transmitted to, and deciphered by, subsequent generations to maintain essential environmental information without permanently altering the genetic code. A more complete understanding of how and when epigenetic inheritance occurs will advance our understanding of numerous different aspects of biology ranging from how organisms cope with changing environments to human pathologies influenced by a parent's environment.


Assuntos
Epigênese Genética , Hereditariedade , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica , Padrões de Herança/genética , Fenótipo
2.
Limnol Oceanogr ; 66(9): 3300-3312, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34690365

RESUMO

The picocyanobacteria Prochlorococcus and Synechococcus are found throughout the ocean's euphotic zone, where the daily light:dark cycle drives their physiology. Periodic deep mixing events can, however, move cells below this region, depriving them of light for extended periods of time. Here, we demonstrate that members of these genera can adapt to tolerate repeated periods of light energy deprivation. Strains kept in the dark for 3 d and then returned to the light initially required 18-26 d to resume growth, but after multiple rounds of dark exposure they began to regrow after only 1-2 d. This dark-tolerant phenotype was stable and heritable; some cultures retained the trait for over 132 generations even when grown in a standard 13:11 light:dark cycle. We found no genetic differences between the dark-tolerant and parental strains of Prochlorococcus NATL2A, indicating that an epigenetic change is likely responsible for the adaptation. To begin to explore this possibility, we asked whether DNA methylation-one potential mechanism mediating epigenetic inheritance in bacteria-occurs in Prochlorococcus. LC-MS/MS analysis showed that while DNA methylations, including 6 mA and 5 mC, are found in some other Prochlorococcus strains, there were no methylations detected in either the parental or dark-tolerant NATL2A strains. These findings suggest that Prochlorococcus utilizes a yet-to-be-determined epigenetic mechanism to adapt to the stress of extended light energy deprivation, and highlights phenotypic heterogeneity as an additional dimension of Prochlorococcus diversity.

3.
BMC Genomics ; 20(1): 445, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159718

RESUMO

BACKGROUND: Directed DNA methylation on N6-adenine (6mA), N4-cytosine (4mC), and C5-cytosine (5mC) can potentially increase DNA coding capacity and regulate a variety of biological functions. These modifications are relatively abundant in bacteria, occurring in about a percent of all bases of most bacteria. Until recently, 5mC and its oxidized derivatives were thought to be the only directed DNA methylation events in metazoa. New and more sensitive detection techniques (ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-ms/ms) and single molecule real-time sequencing (SMRTseq)) have suggested that 6mA and 4mC modifications could be present in a variety of metazoa. RESULTS: Here, we find that both of these techniques are prone to inaccuracies, which overestimate DNA methylation concentrations in metazoan genomic DNA. Artifacts can arise from methylated bacterial DNA contamination of enzyme preparations used to digest DNA and contaminating bacterial DNA in eukaryotic DNA preparations. Moreover, DNA sonication introduces a novel modified base from 5mC that has a retention time near 4mC that can be confused with 4mC. Our analyses also suggest that SMRTseq systematically overestimates 4mC in prokaryotic and eukaryotic DNA and 6mA in DNA samples in which it is rare. Using UHPLC-ms/ms designed to minimize and subtract artifacts, we find low to undetectable levels of 4mC and 6mA in genomes of representative worms, insects, amphibians, birds, rodents and primates under normal growth conditions. We also find that mammalian cells incorporate exogenous methylated nucleosides into their genome, suggesting that a portion of 6mA modifications could derive from incorporation of nucleosides from bacteria in food or microbiota. However, gDNA samples from gnotobiotic mouse tissues found rare (0.9-3.7 ppm) 6mA modifications above background. CONCLUSIONS: Altogether these data demonstrate that 6mA and 4mC are rarer in metazoa than previously reported, and highlight the importance of careful sample preparation and measurement, and need for more accurate sequencing techniques.


Assuntos
Adenina/análogos & derivados , Artefatos , Citosina/análogos & derivados , Metilação de DNA , DNA/genética , Eucariotos/genética , Genoma , Adenina/análise , Adenina/metabolismo , Animais , Células Cultivadas , Citosina/análise , Citosina/metabolismo , Genômica , Humanos , Camundongos , Mioblastos/citologia , Mioblastos/metabolismo
4.
Nat Rev Genet ; 13(5): 343-57, 2012 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-22473383

RESUMO

Organisms require an appropriate balance of stability and reversibility in gene expression programmes to maintain cell identity or to enable responses to stimuli; epigenetic regulation is integral to this dynamic control. Post-translational modification of histones by methylation is an important and widespread type of chromatin modification that is known to influence biological processes in the context of development and cellular responses. To evaluate how histone methylation contributes to stable or reversible control, we provide a broad overview of how histone methylation is regulated and leads to biological outcomes. The importance of appropriately maintaining or reprogramming histone methylation is illustrated by its links to disease and ageing and possibly to transmission of traits across generations.


Assuntos
Histonas/metabolismo , Animais , Caenorhabditis/metabolismo , Drosophila/metabolismo , Epigênese Genética , Feminino , Histona Desmetilases/metabolismo , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Masculino , Metilação , Camundongos , Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional , Ratos
5.
Nature ; 479(7373): 365-71, 2011 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-22012258

RESUMO

Chromatin modifiers regulate lifespan in several organisms, raising the question of whether changes in chromatin states in the parental generation could be incompletely reprogrammed in the next generation and thereby affect the lifespan of descendants. The histone H3 lysine 4 trimethylation (H3K4me3) complex, composed of ASH-2, WDR-5 and the histone methyltransferase SET-2, regulates Caenorhabditis elegans lifespan. Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5 or SET-2 in the parental generation extend the lifespan of descendants up until the third generation. The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendants. Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression. Thus, manipulation of specific chromatin modifiers only in parents can induce an epigenetic memory of longevity in descendants.


Assuntos
Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Epigênese Genética/genética , Padrões de Herança , Longevidade/genética , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Cromatina/metabolismo , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona-Lisina N-Metiltransferase/deficiência , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas , Longevidade/fisiologia , Masculino , Metilação , Mutação/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Linhagem , Proteína 2 de Ligação ao Retinoblastoma/genética , Proteína 2 de Ligação ao Retinoblastoma/metabolismo
6.
Nature ; 466(7304): 383-7, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20555324

RESUMO

The plasticity of ageing suggests that longevity may be controlled epigenetically by specific alterations in chromatin state. The link between chromatin and ageing has mostly focused on histone deacetylation by the Sir2 family, but less is known about the role of other histone modifications in longevity. Histone methylation has a crucial role in development and in maintaining stem cell pluripotency in mammals. Regulators of histone methylation have been associated with ageing in worms and flies, but characterization of their role and mechanism of action has been limited. Here we identify the ASH-2 trithorax complex, which trimethylates histone H3 at lysine 4 (H3K4), as a regulator of lifespan in Caenorhabditis elegans in a directed RNA interference (RNAi) screen in fertile worms. Deficiencies in members of the ASH-2 complex-ASH-2 itself, WDR-5 and the H3K4 methyltransferase SET-2-extend worm lifespan. Conversely, the H3K4 demethylase RBR-2 is required for normal lifespan, consistent with the idea that an excess of H3K4 trimethylation-a mark associated with active chromatin-is detrimental for longevity. Lifespan extension induced by ASH-2 complex deficiency requires the presence of an intact adult germline and the continuous production of mature eggs. ASH-2 and RBR-2 act in the germline, at least in part, to regulate lifespan and to control a set of genes involved in lifespan determination. These results indicate that the longevity of the soma is regulated by an H3K4 methyltransferase/demethylase complex acting in the C. elegans germline.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Células Germinativas/metabolismo , Histonas/metabolismo , Longevidade/fisiologia , Lisina/metabolismo , Complexos Multiproteicos/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Transtornos do Desenvolvimento Sexual , Epigênese Genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Células Germinativas/citologia , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/química , Longevidade/genética , Masculino , Metilação , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Interferência de RNA , Proteína 2 de Ligação ao Retinoblastoma/genética , Proteína 2 de Ligação ao Retinoblastoma/metabolismo
7.
Nat Genet ; 37(11): 1264-9, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16227996

RESUMO

The reduction of iron is an essential step in the transferrin (Tf) cycle, which is the dominant pathway for iron uptake by red blood cell precursors. A deficiency in iron acquisition by red blood cells leads to hypochromic, microcytic anemia. Using a positional cloning strategy, we identified a gene, six-transmembrane epithelial antigen of the prostate 3 (Steap3), responsible for the iron deficiency anemia in the mouse mutant nm1054. Steap3 is expressed highly in hematopoietic tissues, colocalizes with the Tf cycle endosome and facilitates Tf-bound iron uptake. Steap3 shares homology with F(420)H(2):NADP(+) oxidoreductases found in archaea and bacteria, as well as with the yeast FRE family of metalloreductases. Overexpression of Steap3 stimulates the reduction of iron, and mice lacking Steap3 are deficient in erythroid ferrireductase activity. Taken together, these findings indicate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells.


Assuntos
Anemia Ferropriva/metabolismo , Antígenos de Neoplasias/metabolismo , Eritrócitos/enzimologia , FMN Redutase/metabolismo , Ferro/metabolismo , Transferrina/metabolismo , Sequência de Aminoácidos , Animais , Antígenos de Neoplasias/genética , Western Blotting , Células Cultivadas , Endossomos , FMN Redutase/genética , Feminino , Marcação de Genes , Rim/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Oxirredutases , Retroviridae/genética , Homologia de Sequência de Aminoácidos , Frações Subcelulares
8.
Nat Commun ; 14(1): 1617, 2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-36959185

RESUMO

Folate is an essential vitamin for vertebrate embryo development. Methotrexate (MTX) is a folate antagonist that is widely prescribed for autoimmune diseases, blood and solid organ malignancies, and dermatologic diseases. Although it is highly contraindicated for pregnant women, because it is associated with an increased risk of multiple birth defects, the effect of paternal MTX exposure on their offspring has been largely unexplored. Here, we found MTX treatment of adult medaka male fish (Oryzias latipes) causes cranial cartilage defects in their offspring. Small non-coding RNA (sncRNAs) sequencing in the sperm of MTX treated males identify differential expression of a subset of tRNAs, with higher abundance for specific 5' tRNA halves. Sperm RNA methylation analysis on MTX treated males shows that m5C is the most abundant and differential modification found in RNAs ranging in size from 50 to 90 nucleotides, predominantly tRNAs, and that it correlates with greater testicular Dnmt2 methyltransferase expression. Injection of sperm small RNA fractions from MTX-treated males into normal fertilized eggs generated cranial cartilage defects in the offspring. Overall, our data suggest that paternal MTX exposure alters sperm sncRNAs expression and modifications that may contribute to developmental defects in their offspring.


Assuntos
Metotrexato , Pequeno RNA não Traduzido , Animais , Masculino , Gravidez , Humanos , Feminino , Metotrexato/efeitos adversos , Metotrexato/metabolismo , Sêmen , Espermatozoides/metabolismo , Ácido Fólico/metabolismo , Pequeno RNA não Traduzido/genética , RNA de Transferência/genética , RNA de Transferência/metabolismo
9.
Curr Biol ; 17(19): 1646-56, 2007 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-17900900

RESUMO

BACKGROUND: Dietary restriction (DR) is the most effective environmental intervention to extend lifespan in a wide range of species. However, the molecular mechanisms underlying the benefits of DR on longevity are still poorly characterized. AMP-activated protein kinase (AMPK) is activated by a decrease in energy levels, raising the possibility that AMPK might mediate lifespan extension by DR. RESULTS: By using a novel DR assay that we developed and validated in C. elegans, we find that AMPK is required for this DR method to extend lifespan and delay age-dependent decline. We find that AMPK exerts its effects in part via the FOXO transcription factor DAF-16. FOXO/DAF-16 is necessary for the beneficial effects of this DR method on lifespan. Expression of an active version of AMPK in worms increases stress resistance and extends longevity in a FOXO/DAF-16-dependent manner. Lastly, we find that AMPK activates FOXO/DAF-16-dependent transcription and phosphorylates FOXO/DAF-16 at previously unidentified sites, suggesting a possible direct mechanism of regulation of FOXO/DAF-16 by AMPK. CONCLUSIONS: Our study shows that an energy-sensing AMPK-FOXO pathway mediates the lifespan extension induced by a novel method of dietary restriction in C. elegans.


Assuntos
Caenorhabditis elegans/fisiologia , Restrição Calórica , Fatores de Transcrição Forkhead/fisiologia , Longevidade/fisiologia , Complexos Multienzimáticos/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Transdução de Sinais/fisiologia , Proteínas Quinases Ativadas por AMP , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/genética
10.
Oncogene ; 24(50): 7410-25, 2005 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-16288288

RESUMO

A wide range of human diseases, including cancer, has a striking age-dependent onset. However, the molecular mechanisms that connect aging and cancer are just beginning to be unraveled. FOXO transcription factors are promising candidates to serve as molecular links between longevity and tumor suppression. These factors are major substrates of the protein kinase Akt. In the presence of insulin and growth factors, FOXO proteins are relocalized from the nucleus to the cytoplasm and degraded via the ubiquitin-proteasome pathway. In the absence of growth factors, FOXO proteins translocate to the nucleus and upregulate a series of target genes, thereby promoting cell cycle arrest, stress resistance, or apoptosis. Stress stimuli also trigger the relocalization of FOXO factors into the nucleus, thus allowing an adaptive response to stress stimuli. Consistent with the notion that stress resistance is highly coupled with lifespan extension, activation of FOXO transcription factors in worms and flies increases longevity. Emerging evidence also suggests that FOXO factors play a tumor suppressor role in a variety of cancers. Thus, FOXO proteins translate environmental stimuli into changes in gene expression programs that may coordinate organismal longevity and tumor suppression.


Assuntos
Envelhecimento/fisiologia , Transformação Celular Neoplásica , Fatores de Transcrição Forkhead/fisiologia , Regulação da Expressão Gênica , Idade de Início , Animais , Núcleo Celular , Dípteros/fisiologia , Meio Ambiente , Humanos , Longevidade , Mamíferos/fisiologia , Oligoquetos/fisiologia
11.
Cell Rep ; 7(1): 113-26, 2014 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-24685137

RESUMO

How epigenetic information is transmitted from generation to generation remains largely unknown. Deletion of the C. elegans histone H3 lysine 4 dimethyl (H3K4me2) demethylase spr-5 leads to inherited accumulation of the euchromatic H3K4me2 mark and progressive decline in fertility. Here, we identified multiple chromatin-modifying factors, including H3K4me1/me2 and H3K9me3 methyltransferases, an H3K9me3 demethylase, and an H3K9me reader, which either suppress or accelerate the progressive transgenerational phenotypes of spr-5 mutant worms. Our findings uncover a network of chromatin regulators that control the transgenerational flow of epigenetic information and suggest that the balance between euchromatic H3K4 and heterochromatic H3K9 methylation regulates transgenerational effects on fertility.


Assuntos
Caenorhabditis elegans/genética , Histonas/genética , Histonas/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Cromatina/genética , Cromatina/metabolismo , Epigênese Genética , Epigenômica , Metilação , Metiltransferases/metabolismo , Oxirredutases N-Desmetilantes/genética
12.
Cell Metab ; 18(4): 457-9, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-24093670

RESUMO

Reduced folate levels can cause developmental defects and megaloblastic anemia. Padmanabhan et al. (2013) show that mutation in mice of a folate metabolism gene, Mtrr, which encodes for methionine synthase reductase, causes developmental defects not only in the mutant progeny, but also in genetically wild-type descendants for up to four generations.


Assuntos
Anormalidades Congênitas/genética , Embrião de Mamíferos/metabolismo , Epigênese Genética , Ferredoxina-NADP Redutase/genética , Retardo do Crescimento Fetal/genética , Ácido Fólico/metabolismo , Animais , Feminino , Masculino
13.
Aging Cell ; 10(6): 980-90, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21834846

RESUMO

Aging is accompanied by alterations in epigenetic marks that control chromatin states, including histone acetylation and methylation. Enzymes that reversibly affect histone marks associated with active chromatin have recently been found to regulate aging in Caenorhabditis elegans. However, relatively little is known about the importance for aging of histone marks associated with repressed chromatin. Here, we use a targeted RNAi screen in C. elegans to identify four histone demethylases that significantly regulate worm lifespan, UTX-1, RBR-2, LSD-1, and T26A5.5. Interestingly, UTX-1 belongs to a conserved family of histone demethylases specific for lysine 27 of histone H3 (H3K27me3), a mark associated with repressed chromatin. Both utx-1 knockdown and heterozygous mutation of utx-1 extend lifespan and increase the global levels of the H3K27me3 mark in worms. The H3K27me3 mark significantly drops in somatic cells during the normal aging process. UTX-1 regulates lifespan independently of the presence of the germline, but in a manner that depends on the insulin-FoxO signaling pathway. These findings identify the H3K27me3 histone demethylase UTX-1 as a novel regulator of worm lifespan in somatic cells.


Assuntos
Caenorhabditis elegans/metabolismo , Cromatina/metabolismo , Regulação da Expressão Gênica , Histona Desmetilases/metabolismo , Histonas/metabolismo , Longevidade , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo , Animais , Biomarcadores/metabolismo , Western Blotting , Caenorhabditis elegans/genética , Cromatina/genética , Técnicas de Silenciamento de Genes , Células Germinativas/metabolismo , Ensaios de Triagem em Larga Escala , Histona Desmetilases/genética , Histonas/genética , Insulina/metabolismo , Metilação , Reação em Cadeia da Polimerase , Interferência de RNA , Fatores de Transcrição/genética
14.
Aging Cell ; 8(2): 113-27, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19239417

RESUMO

Dietary restriction (DR) has the remarkable ability to extend lifespan and healthspan. A variety of DR regimens have been described in species ranging from yeast to mammals. However, whether different DR regimens extend lifespan via universal, distinct, or overlapping pathways is still an open question. Here we examine the genetic pathways that mediate longevity by different DR regimens in Caenorhabditis elegans. We have previously shown that the low-energy sensing AMP-activated protein kinase AMPK/aak-2 and the Forkhead transcription factor FoxO/daf-16 are necessary for longevity induced by a DR regimen that we developed (sDR). Here we find that AMPK and FoxO are necessary for longevity induced by another DR regimen, but are dispensable for the lifespan extension induced by two different DR methods. Intriguingly, AMPK is also necessary for the lifespan extension elicited by resveratrol, a natural polyphenol that mimics some aspects of DR. Conversely, we test if genes previously reported to mediate longevity by a variety of DR methods are necessary for sDR-induced longevity. Although clk-1, a gene involved in ubiquinone biosynthesis, is also required for sDR-induced lifespan extension, we find that four other genes (sir-2.1, FoxA/pha-4, skn-1, and hsf-1) are all dispensable for longevity induced by sDR. Consistent with the observation that different DR methods extend lifespan by mostly independent genetic mechanisms, we find that the effects on lifespan of two different DR regimens are additive. Understanding the genetic network by which different DR regimens extend lifespan has important implications for harnessing the full benefits of DR on lifespan and healthspan.


Assuntos
Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Restrição Calórica/métodos , Privação de Alimentos/fisiologia , Alimentos Formulados , Longevidade/fisiologia , Transdução de Sinais/genética , Quinases Proteína-Quinases Ativadas por AMP , Animais , Antioxidantes/farmacologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Longevidade/efeitos dos fármacos , Proteínas Quinases/metabolismo , Resveratrol , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/metabolismo , Estilbenos/farmacologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo
15.
Ann N Y Acad Sci ; 1170: 688-92, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19686213

RESUMO

Aging is regulated by modifications in single genes and by simple changes in the environment. The signaling pathway connecting insulin to FoxO transcription factors integrates environmental stimuli to regulate lifespan. FoxO transcription factors are directly phosphorylated in response to insulin/growth factor signaling by the protein kinase Akt, thereby causing their sequestration in the cytoplasm. In the absence of insulin/growth factors, FoxO factors translocate to the nucleus where they trigger a range of cellular responses, including resistance to oxidative stress--a phenotype highly coupled with lifespan extension. Our recent results indicate that FoxO transcription factors are also regulated in response to nutrient deprivation by the AMP-activated protein kinase (AMPK) pathway. The energy-sensing AMPK directly phosphorylates FoxO transcription factors at six regulatory sites. AMPK phosphorylation enhances FoxO transcriptional activity, leading to the expression of specific target genes involved in stress resistance and changes in energy metabolism. The AMPK-FoxO pathway plays a crucial role in the ability of a dietary restriction regimen to extend lifespan in Caenorhabditis elegans. Understanding the intricate signaling networks that translate environmental conditions like dietary restriction into changes in gene expression that extend lifespan will be of critical importance to identify ways to delay the onset of aging and age-dependent diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Longevidade , Fatores de Transcrição/metabolismo , Animais , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Regulação da Expressão Gênica , Fosforilação
16.
J Biol Chem ; 282(41): 30107-19, 2007 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-17711846

RESUMO

The maintenance of homeostasis throughout an organism's life span requires constant adaptation to changes in energy levels. The AMP-activated protein kinase (AMPK) plays a critical role in the cellular responses to low energy levels by switching off energy-consuming pathways and switching on energy-producing pathways. However, the transcriptional mechanisms by which AMPK acts to adjust cellular energy levels are not entirely characterized. Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites. Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. Using a genome-wide microarray analysis, we identify a set of target genes that are regulated by FOXO3 when phosphorylated at these six regulatory sites in mammalian cells. The regulation of FOXO3 by AMPK may play a crucial role in fine tuning gene expression programs that control energy balance and stress resistance in cells throughout life.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Complexos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases Ativadas por AMP , Sequência de Aminoácidos , Animais , Linhagem Celular , Proteína Forkhead Box O3 , Regulação da Expressão Gênica , Humanos , Luciferases/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Dados de Sequência Molecular , Fosforilação , Transcrição Gênica
17.
Hum Mol Genet ; 15(6): 953-64, 2006 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16467350

RESUMO

Proteins with iron-sulfur (Fe-S) clusters participate in multiple metabolic pathways throughout the cell. The mitochondrial ABC half-transporter Abcb7, which is mutated in X-linked sideroblastic anemia with ataxia in humans, is a functional ortholog of yeast Atm1p and is predicted to export a mitochondrially derived metabolite required for cytosolic Fe-S cluster assembly. Using an inducible Cre/loxP system to delete exons 9 and 10 of the Abcb7 gene, we examined the phenotype of mice deficient in Abcb7. We found that Abcb7 was essential in extra-embryonic tissues early in gestation and that the mutant allele exhibits an X-linked parent-of-origin lethality effect. Furthermore, using X-chromosome inactivation assays and tissue-specific deletions, Abcb7 was found to be essential for the development and function of numerous other cell types and tissues. A notable exception to this was liver, where loss of Abcb7 impaired cytosolic Fe-S cluster assembly but was not lethal. In this situation, control of iron regulatory protein 1, a key cytosolic modulator of iron metabolism, which is responsive to the availability of cytosolic Fe-S clusters, was impaired and contributed to the dysregulation of hepatocyte iron metabolism. Altogether, these studies demonstrate the essential nature of Abcb7 in mammals and further substantiate a central role for mitochondria in the biogenesis of cytosolic Fe-S proteins.


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Citosol/metabolismo , Proteínas Ferro-Enxofre/biossíntese , Proteínas Mitocondriais/fisiologia , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Linhagem Celular , Linhagem da Célula/genética , Genes Letais , Hepatócitos/metabolismo , Hepatócitos/ultraestrutura , Ferro/metabolismo , Proteína 1 Reguladora do Ferro/metabolismo , Proteína 2 Reguladora do Ferro/metabolismo , Masculino , Camundongos , Proteínas Mitocondriais/deficiência , Proteínas Mitocondriais/genética , Cromossomo X/genética
18.
Blood ; 106(8): 2879-83, 2005 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-15961514

RESUMO

Mammalian nonheme iron absorption requires reduction of dietary iron for uptake by the divalent metal ion transport system in the intestine. This was thought to be mediated by duodenal cytochrome b (Cybrd1), a ferric reductase enzyme resident on the luminal surface of intestinal absorptive cells. To test its importance in vivo, we inactivated the murine Cybrd1 gene and assessed tissue iron stores in Cybrd1-null mice. We found that loss of Cybrd1 had little or no impact on body iron stores, even in the setting of iron deficiency. We conclude that other mechanisms must be available for the reduction of dietary iron.


Assuntos
Grupo dos Citocromos b/metabolismo , Duodeno/metabolismo , Ferro da Dieta/metabolismo , Oxirredutases/metabolismo , Absorção , Animais , Grupo dos Citocromos b/deficiência , Grupo dos Citocromos b/genética , Fígado/metabolismo , Camundongos , Camundongos Knockout , Mutação/genética , Oxirredutases/deficiência , Oxirredutases/genética , Fenótipo
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