Nature (London), 2011-08, Vol.476 (7361), p.467-471
2011
Details
- Autor(en) / Beteiligte
- Titel
- A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation
- Ist Teil von
- Nature (London), 2011-08, Vol.476 (7361), p.467-471
- Ort / Verlag
- London: Nature Publishing Group
- Erscheinungsjahr
- 2011
- Link zum Volltext
- Quelle
- EBSCOhost Psychology and Behavioral Sciences Collection
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687DOI: 10.1038/nature10312Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3179485
- Format
- –
- Schlagworte
- Animals, Antigen receptors, T cell, Biological and medical sciences, Cell cycle, Cell Cycle Proteins - genetics, Cell Cycle Proteins - metabolism, Cell Differentiation, Cell division, Chromosomal Proteins, Non-Histone - deficiency, Chromosomal Proteins, Non-Histone - genetics, Chromosomal Proteins, Non-Histone - metabolism, Cohesins, DNA binding proteins, Experiments, Fundamental and applied biological sciences. Psychology, Fundamental immunology, Gene Expression Regulation, Gene Rearrangement, T-Lymphocyte - genetics, Genes, RAG-1 - genetics, Genetic aspects, Genetics of the immune response, Immunobiology, Mice, Nuclear Proteins - deficiency, Nuclear Proteins - genetics, Nuclear Proteins - metabolism, Phosphoproteins - deficiency, Phosphoproteins - genetics, Phosphoproteins - metabolism, Physiological aspects, Proteins, Receptors, Receptors, Antigen, T-Cell, alpha-beta - genetics, Receptors, Antigen, T-Cell, alpha-beta - metabolism, Recombinases - metabolism, T cells, Thymus Gland - cytology, Thymus Gland - metabolism, Transcription, Genetic