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Regulation of interleukin 7–dependent immunoglobulin heavy-chain variable gene rearrangements by transcription factor STAT5

Nature Immunology volume 6, pages 836–843 (2005)Cite this article

Abstract

Rearrangement of immunoglobulin heavy-chain variable (VH) gene segments has been suggested to be regulated by interleukin 7 signaling in pro–B cells. However, the genetic evidence for this recombination pathway has been challenged. Furthermore, no molecular components that directly control VH gene rearrangement have been elucidated. Using mice deficient in the interleukin 7–activated transcription factor STAT5, we demonstrate here that STAT5 regulated germline transcription, histone acetylation and DNA recombination of distal VH gene segments. STAT5 associated with VH gene segments in vivo and was recruited as a coactivator with the transcription factor Oct-1. STAT5 did not affect the nuclear repositioning or compaction of the immunoglobulin heavy-chain locus. Therefore, STAT5 functions at a distinct step in regulating distal VH recombination in relation to the transcription factor Pax5 and histone methyltransferase Ezh2.

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Figure 1: STAT5 regulates rearrangement and germline transcription of distal VHJ558 genes.
Figure 2: STAT5 is required for distal VHJ558 gene transcription but not for nuclear repositioning and compaction of the Igh locus.
Figure 3: STAT5 crosslinks to VHJ558 promoters and regulates histone acetylation.
Figure 4: IL-7 signaling regulates VHJ558 germline transcription, histone acetylation and STAT5 binding in vivo.
Figure 5: Oct-1 can mediate STAT5 recruitment to VHJ558 promoters.

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Acknowledgements

We thank members of the laboratory for comments and criticisms. Supported by the Irvington Institute (K.L.M.) and Howard Hughes Medical Institute (H.S.)

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Authors and Affiliations

  1. Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, 60637, Illinois, USA

    Eric Bertolino, Karen Reddy, Kay L Medina & Harinder Singh

  2. Howard Hughes Medical Institute, The University of Chicago, Chicago, 60637, Illinois, USA

    Karen Reddy & Harinder Singh

  3. Department of Biochemistry, Howard Hughes Medical Institute St. Jude's Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Evan Parganas & James Ihle

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Correspondence to Harinder Singh.

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Supplementary information

Supplementary Fig. 1

STAT5 regulates rearrangement of distal VHJ558 genes. (PDF 391 kb)

Supplementary Fig. 2

DNA sequences analysis of VHJ558 family members. (PDF 4512 kb)

Supplementary Fig. 3

STAT5 regulates histone acetylation and Oct-1 binding to VHJ558 promoters. (PDF 300 kb)

Supplementary Fig. 4

Immunoblot analysis of STAT5, Oct-1 and TBP in response to IL-7 signaling in Rag2−/− pro-B cells. (PDF 496 kb)

Supplementary Fig. 5

Gel shift assays with VH or VHmut J558 oligonucleotide duplexes described in Fig. 5 (PDF 277 kb)

Supplementary Table 1

The sequence of forward (U) and reverse (L) primers used for PCR in the RT-PCR, gene rearrangement and Chip assays are indicated. (PDF 22 kb)

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Bertolino, E., Reddy, K., Medina, K. et al. Regulation of interleukin 7–dependent immunoglobulin heavy-chain variable gene rearrangements by transcription factor STAT5. Nat Immunol 6, 836–843 (2005). https://doi.org/10.1038/ni1226

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