Imperial College London
Alternate

ProfessorLuisAragon Alcaide

Faculty of Medicine, Institute of Clinical Sciences

Professor of Genetics
 
 
 
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Contact

 

+44 (0)20 3313 8013luis.aragon

 
 
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Location

 

CRB (Clinical Research Building)Hammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Seitan:2011:10.1038/nature10312,
author = {Seitan, VC and Hao, B and Tachibana-Konwalski, K and Lavagnolli, T and Mira-Bontenbal, H and Brown, KE and Teng, G and Carroll, T and Terry, A and Horan, K and Marks, H and Adams, DJ and Schatz, DG and Aragon, L and Fisher, AG and Krangel, MS and Nasmyth, K and Merkenschlager, M},
doi = {10.1038/nature10312},
journal = {Nature},
pages = {467--U126},
title = {A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation},
url = {http://dx.doi.org/10.1038/nature10312},
volume = {476},
year = {2011}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Cohesin enables post-replicative DNA repair and chromosome segregation by holding sister chromatids together from the time of DNA replication in S phase until mitosis1. There is growing evidence that cohesin also forms long-range chromosomal cis-interactions2,3,4 and may regulate gene expression2,3,4,5,6,7,8,9,10 in association with CTCF8,9, mediator4 or tissue-specific transcription factors10. Human cohesinopathies such as Cornelia de Lange syndrome are thought to result from impaired non-canonical cohesin functions7, but a clear distinction between the cell-division-related and cell-division-independent functions of cohesion—as exemplified in Drosophila11,12,13—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 machinery14,15 and Tcra rearrangement. Provision of pre-rearranged TCR transgenes largely rescued thymocyte differentiation, demonstrating that among thousands of potential target genes across the genome4,8,9,10, 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 mammali
AU  - Seitan,VC
AU  - Hao,B
AU  - Tachibana-Konwalski,K
AU  - Lavagnolli,T
AU  - Mira-Bontenbal,H
AU  - Brown,KE
AU  - Teng,G
AU  - Carroll,T
AU  - Terry,A
AU  - Horan,K
AU  - Marks,H
AU  - Adams,DJ
AU  - Schatz,DG
AU  - Aragon,L
AU  - Fisher,AG
AU  - Krangel,MS
AU  - Nasmyth,K
AU  - Merkenschlager,M
DO  - 10.1038/nature10312
EP  - 126
PY  - 2011///
SN  - 0028-0836
SP  - 467
TI  - A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation
T2  - Nature
UR  - http://dx.doi.org/10.1038/nature10312
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000294209400040&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/71590
VL  - 476
ER  -
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