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1.
Mol Cell ; 49(1): 67-79, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23177737

RESUMO

Elucidating the global function of a transcription factor implies the identification of its target genes and genomic binding sites. The role of chromatin in this context is unclear, but the dominant view is that factors bind preferentially to nucleosome-depleted regions identified as DNaseI-hypersensitive sites (DHS). Here we show by ChIP, MNase, and DNaseI assays followed by deep sequencing that the progesterone receptor (PR) requires nucleosomes for optimal binding and function. In breast cancer cells treated with progestins, we identified 25,000 PR binding sites (PRbs). The majority of these sites encompassed several copies of the hexanucleotide TGTYCY, which is highly abundant in the genome. We found that functional PRbs accumulate around progesterone-induced genes, mainly in enhancers. Most of these sites overlap with DHS but exhibit high nucleosome occupancy. Progestin stimulation results in remodeling of these nucleosomes with displacement of histones H1 and H2A/H2B dimers. Our results strongly suggest that nucleosomes are crucial for PR binding and hormonal gene regulation.


Assuntos
Nucleossomos/metabolismo , Receptores de Progesterona/metabolismo , Fatores de Transcrição/metabolismo , Ativação Transcricional , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Montagem e Desmontagem da Cromatina , Imunoprecipitação da Cromatina , Mapeamento Cromossômico , Sequência Consenso , Sequenciamento de Nucleotídeos em Larga Escala , Histonas/metabolismo , Humanos , Nucleossomos/fisiologia , Progestinas/fisiologia , Ligação Proteica , Elementos de Resposta , Análise de Sequência de DNA
2.
Genes Dev ; 25(8): 845-62, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21447625

RESUMO

Gene regulation by external signals requires access of transcription factors to DNA sequences of target genes, which is limited by the compaction of DNA in chromatin. Although we have gained insight into how core histones and their modifications influence this process, the role of linker histones remains unclear. Here we show that, within the first minute of progesterone action, a complex cooperation between different enzymes acting on chromatin mediates histone H1 displacement as a requisite for gene induction and cell proliferation. First, activated progesterone receptor (PR) recruits the chromatin remodeling complexes NURF and ASCOM (ASC-2 [activating signal cointegrator-2] complex) to hormone target genes. The trimethylation of histone H3 at Lys 4 by the MLL2/MLL3 subunits of ASCOM, enhanced by the hormone-induced displacement of the H3K4 demethylase KDM5B, stabilizes NURF binding. NURF facilitates the PR-mediated recruitment of Cdk2/CyclinA, which is required for histone H1 displacement. Cooperation of ATP-dependent remodeling, histone methylation, and kinase activation, followed by H1 displacement, is a prerequisite for the subsequent displacement of histone H2A/H2B catalyzed by PCAF and BAF. Chromatin immunoprecipitation (ChIP) and sequencing (ChIP-seq) and expression arrays show that H1 displacement is required for hormone induction of most hormone target genes, some of which are involved in cell proliferation.


Assuntos
Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas Nucleares/metabolismo , Promegestona/farmacologia , Proteínas Repressoras/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Montagem e Desmontagem da Cromatina , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Histonas , Humanos , Imunoprecipitação , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Interferência de RNA , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição de p300-CBP/genética
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