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A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation.
Nature ; 476(7361): 467-71, 2011 Aug 10.
Article em En | MEDLINE | ID: mdl-21832993
Cohesin enables post-replicative DNA repair and chromosome segregation by holding sister chromatids together from the time of DNA replication in S phase until mitosis. There is growing evidence that cohesin also forms long-range chromosomal cis-interactions and may regulate gene expression in association with CTCF, mediator or tissue-specific transcription factors. Human cohesinopathies such as Cornelia de Lange syndrome are thought to result from impaired non-canonical cohesin functions, but a clear distinction between the cell-division-related and cell-division-independent functions of cohesion--as exemplified in Drosophila--has not been demonstrated in vertebrate systems. To address this, here we deleted the cohesin locus Rad21 in mouse thymocytes at a time in development when these cells stop cycling and rearrange their T-cell receptor (TCR) α locus (Tcra). Rad21-deficient thymocytes had a normal lifespan and retained the ability to differentiate, albeit with reduced efficiency. Loss of Rad21 led to defective chromatin architecture at the Tcra locus, where cohesion-binding sites flank the TEA promoter and the Eα enhancer, and demarcate Tcra from interspersed Tcrd elements and neighbouring housekeeping genes. Cohesin was required for long-range promoter-enhancer interactions, Tcra transcription, H3K4me3 histone modifications that recruit the recombination machinery and Tcra rearrangement. Provision of pre-rearranged TCR transgenes largely rescued thymocyte differentiation, demonstrating that among thousands of potential target genes across the genome, defective Tcra rearrangement was limiting for the differentiation of cohesin-deficient thymocytes. These findings firmly establish a cell-division-independent role for cohesin in Tcra locus rearrangement and provide a comprehensive account of the mechanisms by which cohesin enables cellular differentiation in a well-characterized mammalian system.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfoproteínas / Timo / Proteínas Nucleares / Proteínas Cromossômicas não Histona / Rearranjo Gênico do Linfócito T / Diferenciação Celular / Receptores de Antígenos de Linfócitos T alfa-beta / Proteínas de Ciclo Celular Limite: Animals Idioma: En Ano de publicação: 2011 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfoproteínas / Timo / Proteínas Nucleares / Proteínas Cromossômicas não Histona / Rearranjo Gênico do Linfócito T / Diferenciação Celular / Receptores de Antígenos de Linfócitos T alfa-beta / Proteínas de Ciclo Celular Limite: Animals Idioma: En Ano de publicação: 2011 Tipo de documento: Article