A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation

Title: A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation
Authors: Seitan, VC
Hao, B
Tachibana-Konwalski, K
Lavagnolli, T
Mira-Bontenbal, H
Brown, KE
Teng, G
Carroll, T
Terry, A
Horan, K
Marks, H
Adams, DJ
Schatz, DG
Aragon, L
Fisher, AG
Krangel, MS
Nasmyth, K
Merkenschlager, M
Item Type: Journal Article
Abstract: 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 mammalian system.
Issue Date: 25-Aug-2011
Date of Acceptance: 20-Jun-2011
URI: http://hdl.handle.net/10044/1/71590
DOI: https://doi.org/10.1038/nature10312
ISSN: 0028-0836
Publisher: Nature Research
Start Page: 467
End Page: U126
Journal / Book Title: Nature
Volume: 476
Copyright Statement: © 2011 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1038/nature10312.
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: PO4050659629
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
ANTIGEN-RECEPTOR
CHROMATIN ARCHITECTURE
V(D)J RECOMBINATION
POSITIVE SELECTION
TRANSGENIC MICE
DAD1 GENES
TCR-ALPHA
ACCESSIBILITY
REGION
LOCUS
Animals
Cell Cycle Proteins
Cell Differentiation
Chromosomal Proteins, Non-Histone
Gene Expression Regulation
Gene Rearrangement, T-Lymphocyte
Genes, RAG-1
Mice
Nuclear Proteins
Phosphoproteins
Receptors, Antigen, T-Cell, alpha-beta
Recombinases
Thymus Gland
Transcription, Genetic
Thymus Gland
Animals
Mice
Recombinases
Cell Cycle Proteins
Receptors, Antigen, T-Cell, alpha-beta
Nuclear Proteins
Chromosomal Proteins, Non-Histone
Phosphoproteins
Cell Differentiation
Gene Rearrangement, T-Lymphocyte
Transcription, Genetic
Gene Expression Regulation
Genes, RAG-1
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
ANTIGEN-RECEPTOR
CHROMATIN ARCHITECTURE
V(D)J RECOMBINATION
POSITIVE SELECTION
TRANSGENIC MICE
DAD1 GENES
TCR-ALPHA
ACCESSIBILITY
REGION
LOCUS
MD Multidisciplinary
General Science & Technology
Publication Status: Published
Online Publication Date: 2011-08-10
Appears in Collections:Clinical Sciences
Molecular Sciences



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