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1.
J Cell Biol ; 218(3): 820-838, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30737265

RESUMO

The segregation of the genome into accessible euchromatin and histone H3K9-methylated heterochromatin helps silence repetitive elements and tissue-specific genes. In Caenorhabditis elegans, MET-2, the homologue of mammalian SETDB1, catalyzes H3K9me1 and me2, yet like SETDB1, its regulation is enigmatic. Contrary to the cytosolic enrichment of overexpressed MET-2, we show that endogenous MET-2 is nuclear throughout development, forming perinuclear foci in a cell cycle-dependent manner. Mass spectrometry identified two cofactors that bind MET-2: LIN-65, a highly unstructured protein, and ARLE-14, a conserved GTPase effector. All three factors colocalize in heterochromatic foci. Ablation of lin-65, but not arle-14, mislocalizes and destabilizes MET-2, resulting in decreased H3K9 dimethylation, dispersion of heterochromatic foci, and derepression of MET-2 targets. Mutation of met-2 or lin-65 also disrupts the perinuclear anchoring of genomic heterochromatin. Loss of LIN-65, like that of MET-2, compromises temperature stress resistance and germline integrity, which are both linked to promiscuous repeat transcription and gene expression.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Ciclo Celular , Regulação da Expressão Gênica , Resposta ao Choque Térmico , Heterocromatina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Transcrição Gênica , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Heterocromatina/genética , Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Histonas/metabolismo , Metilação , Mutação , Ligação Proteica
2.
Genome Biol ; 16: 206, 2015 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-26399229

RESUMO

BACKGROUND: The spatiotemporal behavior of chromatin is an important control mechanism of genomic function. Studies in Saccharomyces cerevisiae have broadly contributed to demonstrate the functional importance of nuclear organization. Although in the wild yeast survival depends on their ability to withstand adverse conditions, most of these studies were conducted on cells undergoing exponential growth. In these conditions, as in most eukaryotic cells, silent chromatin that is mainly found at the 32 telomeres accumulates at the nuclear envelope, forming three to five foci. RESULTS: Here, combining live microscopy, DNA FISH and chromosome conformation capture (HiC) techniques, we report that chromosomes adopt distinct organizations according to the metabolic status of the cell. In particular, following carbon source exhaustion the genome of long-lived quiescent cells undergoes a major spatial re-organization driven by the grouping of telomeres into a unique focus or hypercluster localized in the center of the nucleus. This change in genome conformation is specific to quiescent cells able to sustain long-term viability. We further show that reactive oxygen species produced by mitochondrial activity during respiration commit the cell to form a hypercluster upon starvation. Importantly, deleting the gene encoding telomere associated silencing factor SIR3 abolishes telomere grouping and decreases longevity, a defect that is rescued by expressing a silencing defective SIR3 allele competent for hypercluster formation. CONCLUSIONS: Our data show that mitochondrial activity primes cells to group their telomeres into a hypercluster upon starvation, reshaping the genome architecture into a conformation that may contribute to maintain longevity of quiescent cells.


Assuntos
Fase de Repouso do Ciclo Celular/genética , Telômero/ultraestrutura , Carbono/metabolismo , Centrômero , Cromossomos Fúngicos , Espécies Reativas de Oxigênio/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/genética
3.
Brain Pathol ; 20(2): 481-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19775291

RESUMO

Although leptin and its receptor (ObR) have emerged as important cancer biomarkers, the role of the leptin system in brain tumor development remains unknown. We screened 87 human brain tumor biopsies using immunohistochemistry and detected leptin and ObR in 55.2% and 60.9% cases, respectively. In contrast, leptin and ObR were absent in 14 samples of normal brain tissue. The presence of leptin correlated with ObR with overall concordance 80.5%. The leptin/ObR system was highly expressed in glioblastomas and anaplastic astrocytomas, while lower expression of both markers was noted in low-grade astrocytomas and gangliogliomas. The association between leptin/ObR and the degree of tumor malignancy was highly significant (P < 0.001). Using double immunofluorescence of glioblastoma tissues, we found co-expression of leptin with ObR and with the proliferation marker Ki-67 in 87% and 64% of cells, respectively. The leptin/ObR-positive tissues also expressed activated forms of STAT3 and Akt. In line with this finding, ObR-positive glioblastoma cells responded to leptin with cell growth and induction of the STAT3 and Akt pathways as well as inactivation of the cell cycle suppressor Rb. In summary, our data demonstrate that the leptin/ObR system is expressed in malignant brain tumors and might be involved in tumor progression.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Glioma/patologia , Leptina/metabolismo , Receptores para Leptina/metabolismo , Western Blotting , Encéfalo/metabolismo , Encéfalo/patologia , Contagem de Células , Linhagem Celular Tumoral , Proliferação de Células , Imunofluorescência , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Proteína Oncogênica v-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
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