Skip to main content
Journal cover image

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

Publication ,  Journal Article
Seitan, VC; Hao, B; Tachibana-Konwalski, K; Lavagnolli, T; Mira-Bontenbal, H; Brown, KE; Teng, G; Carroll, T; Terry, A; Horan, K; Marks, H ...
Published in: Nature
August 10, 2011

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 10, 2011

Volume

476

Issue

7361

Start / End Page

467 / 471

Location

England

Related Subject Headings

  • Transcription, Genetic
  • Thymus Gland
  • Recombinases
  • Receptors, Antigen, T-Cell, alpha-beta
  • Phosphoproteins
  • Nuclear Proteins
  • Mice
  • Genes, RAG-1
  • General Science & Technology
  • Gene Rearrangement, T-Lymphocyte
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Seitan, V. C., Hao, B., Tachibana-Konwalski, K., Lavagnolli, T., Mira-Bontenbal, H., Brown, K. E., … Merkenschlager, M. (2011). A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation. Nature, 476(7361), 467–471. https://doi.org/10.1038/nature10312
Seitan, Vlad C., Bingtao Hao, Kikuë Tachibana-Konwalski, Thais Lavagnolli, Hegias Mira-Bontenbal, Karen E. Brown, Grace Teng, et al. “A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation.Nature 476, no. 7361 (August 10, 2011): 467–71. https://doi.org/10.1038/nature10312.
Seitan VC, Hao B, Tachibana-Konwalski K, Lavagnolli T, Mira-Bontenbal H, Brown KE, et al. A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation. Nature. 2011 Aug 10;476(7361):467–71.
Seitan, Vlad C., et al. “A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation.Nature, vol. 476, no. 7361, Aug. 2011, pp. 467–71. Pubmed, doi:10.1038/nature10312.
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. A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation. Nature. 2011 Aug 10;476(7361):467–471.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 10, 2011

Volume

476

Issue

7361

Start / End Page

467 / 471

Location

England

Related Subject Headings

  • Transcription, Genetic
  • Thymus Gland
  • Recombinases
  • Receptors, Antigen, T-Cell, alpha-beta
  • Phosphoproteins
  • Nuclear Proteins
  • Mice
  • Genes, RAG-1
  • General Science & Technology
  • Gene Rearrangement, T-Lymphocyte