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Regulation of T cell receptor-α gene recombination by transcription

Nature Immunology volume 7, pages 1109–1115 (2006)Cite this article

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Abstract

Despite the longstanding correlation between transcription and variable-(diversity)-joining (V(D)J) recombination, it is unknown whether transcription itself can direct recombinase targeting. Here we show that blockade of transcriptional elongation through the mouse T cell receptor-α (Tcra) locus suppressed Vα-to-Jα recombination and chromatin remodeling of Jα segments. Transcriptional blockade also derepressed cryptic Jα promoters. Our results demonstrate two key functions for transcription in Tcra locus regulation. Transcription increases the recombination of Jα segments located within several kilobases of a promoter and prevents the activation of downstream promoters through transcriptional interference. These influences promote an ordered progression of Tcra locus recombination events and selection of a robust Tcra repertoire.

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Figure 1: Tcra locus and gene targeting.
Figure 2: Transcription termination in 56R mice.
Figure 3: Jα use and rearrangements in 56R and 56I mice.
Figure 4: Jα histone modifications in 56R mice.
Figure 5: Jα germline transcription in 56R mice.

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Change history

  • 07 September 2006

    In the version of this article initially published online, the third sentence of the third paragraph of the results section is incorrect. The correct sentence is "We reasoned that a phenotype change resulting from the 56R approach could result from sequence deletion, whereas a phenotype change resulting from the 56I approach could result from the increased distance between Jα segments." The error has been corrected for all versions of the article.

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Acknowledgements

We thank C. Bock (Duke University Knockout and Transgenic Mouse Resource) for the production of gene-targeted mice; L. Esper for technical assistance; H. Scrable (University of Virginia, Charlottesville, Virginia) for lacI mouse embryo fibroblasts; and B. Sleckman (Washington University School of Medicine, St. Louis, Missouri), E. Oltz (Vanderbilt University, Nashville, Tennessee), Y. Zhuang and T. Kepler for comments on the manuscript and advice. Supported by the National Institutes of Health (GM41052 to M.S.K.).

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Authors and Affiliations

  1. Department of Immunology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Iratxe Abarrategui & Michael S Krangel

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  1. Iratxe Abarrategui
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  2. Michael S Krangel
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Contributions

I.A. did all the experiments; M.S.K. supervised the work; and I.A. and M.S.K. prepared the manuscript.

Corresponding author

Correspondence to Michael S Krangel.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Luciferase assay. (PDF 80 kb)

Supplementary Table 1

Oligonucleotides for RT-PCR analysis of nuclear transcripts. (PDF 49 kb)

Supplementary Table 2

Oligonucleotides for nuclear run-on assay. (PDF 51 kb)

Supplementary Table 3

Oligonucleotides for Vα-to-Jα rearrangement analysis. (PDF 52 kb)

Supplementary Table 4

Oligonucleotides for chromatin immunoprecipitation analysis. (PDF 52 kb)

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Abarrategui, I., Krangel, M. Regulation of T cell receptor-α gene recombination by transcription. Nat Immunol 7, 1109–1115 (2006). https://doi.org/10.1038/ni1379

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