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1.
PLoS Genet ; 10(2): e1004153, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24550742

RESUMO

The cohesin complex is crucial for chromosome segregation during mitosis and has recently also been implicated in transcriptional regulation and chromatin architecture. The NIPBL protein is required for the loading of cohesin onto chromatin, but how and where cohesin is loaded in vertebrate cells is unclear. Heterozygous mutations of NIPBL were found in 50% of the cases of Cornelia de Lange Syndrome (CdLS), a human developmental syndrome with a complex phenotype. However, no defects in the mitotic function of cohesin have been observed so far and the links between NIPBL mutations and the observed developmental defects are unclear. We show that NIPBL binds to chromatin in somatic cells with a different timing than cohesin. Further, we observe that high-affinity NIPBL binding sites localize to different regions than cohesin and almost exclusively to the promoters of active genes. NIPBL or cohesin knockdown reduce transcription of these genes differently, suggesting a cohesin-independent role of NIPBL for transcription. Motif analysis and comparison to published data show that NIPBL co-localizes with a specific set of other transcription factors. In cells derived from CdLS patients NIPBL binding levels are reduced and several of the NIPBL-bound genes have previously been observed to be mis-expressed in CdLS. In summary, our observations indicate that NIPBL mutations might cause developmental defects in different ways. First, defects of NIPBL might lead to cohesin-loading defects and thereby alter gene expression and second, NIPBL deficiency might affect genes directly via its role at the respective promoters.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Cornélia de Lange/genética , Proteínas/genética , Transcrição Gênica , Fator de Ligação a CCCTC , Proteínas de Ciclo Celular/metabolismo , Cromatina/genética , Proteínas Cromossômicas não Histona/metabolismo , Segregação de Cromossomos/genética , Síndrome de Cornélia de Lange/patologia , Regulação da Expressão Gênica , Genoma Humano , Humanos , Mutação , Regiões Promotoras Genéticas , Proteínas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Coesinas
2.
Proc Natl Acad Sci U S A ; 111(3): 996-1001, 2014 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-24335803

RESUMO

Recent studies of genome-wide chromatin interactions have revealed that the human genome is partitioned into many self-associating topological domains. The boundary sequences between domains are enriched for binding sites of CTCC-binding factor (CTCF) and the cohesin complex, implicating these two factors in the establishment or maintenance of topological domains. To determine the role of cohesin and CTCF in higher-order chromatin architecture in human cells, we depleted the cohesin complex or CTCF and examined the consequences of loss of these factors on higher-order chromatin organization, as well as the transcriptome. We observed a general loss of local chromatin interactions upon disruption of cohesin, but the topological domains remain intact. However, we found that depletion of CTCF not only reduced intradomain interactions but also increased interdomain interactions. Furthermore, distinct groups of genes become misregulated upon depletion of cohesin and CTCF. Taken together, these observations suggest that CTCF and cohesin contribute differentially to chromatin organization and gene regulation.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Cromatina/química , Proteínas Cromossômicas não Histona/metabolismo , Regulação da Expressão Gênica , Proteínas Repressoras/metabolismo , Sítios de Ligação , Fator de Ligação a CCCTC , Linhagem Celular , Núcleo Celular/metabolismo , Cromatina/metabolismo , Proteínas de Ligação a DNA , Perfilação da Expressão Gênica , Células HEK293 , Proteínas de Homeodomínio/metabolismo , Humanos , Mitose , Família Multigênica , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Transcriptoma , Coesinas
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