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    Publication Date: 2011-08-13
    Description: 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) alpha 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 Ealpha 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.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seitan, Vlad C -- Hao, Bingtao -- Tachibana-Konwalski, Kikue -- Lavagnolli, Thais -- Mira-Bontenbal, Hegias -- Brown, Karen E -- Teng, Grace -- Carroll, Tom -- Terry, Anna -- Horan, Katie -- Marks, Hendrik -- Adams, David J -- Schatz, David G -- Aragon, Luis -- Fisher, Amanda G -- Krangel, Michael S -- Nasmyth, Kim -- Merkenschlager, Matthias -- 13031/Cancer Research UK/United Kingdom -- MC_U120027516/Medical Research Council/United Kingdom -- MC_U120081295/Medical Research Council/United Kingdom -- R37 AI032524/AI/NIAID NIH HHS/ -- R37 AI032524-20/AI/NIAID NIH HHS/ -- R37 GM041052/GM/NIGMS NIH HHS/ -- R37 GM041052-22/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2011 Aug 10;476(7361):467-71. doi: 10.1038/nature10312.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Cycle Proteins/genetics/*metabolism ; *Cell Differentiation ; Chromosomal Proteins, Non-Histone/deficiency/genetics/*metabolism ; Gene Expression Regulation ; *Gene Rearrangement, T-Lymphocyte/genetics ; Genes, RAG-1/genetics ; Mice ; Nuclear Proteins/deficiency/genetics/*metabolism ; Phosphoproteins/deficiency/genetics/*metabolism ; Receptors, Antigen, T-Cell, alpha-beta/*genetics/*metabolism ; Recombinases/metabolism ; Thymus Gland/*cytology/metabolism ; Transcription, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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