Regulation of V(D)J Recombination by Transcriptional Promoters

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 1999 Mar 19

PMID 10082543

Citations 22

Authors

M L Sikes

C C Suarez

E M Oltz

Affiliations

Soon will be listed here.

Abstract

Enhancer elements potentiate the rearrangement of antigen receptor loci via changes in the accessibility of gene segment clusters to V(D)J recombinase. Here, we show that enhancer activity per se is insufficient to target T-cell receptor beta miniloci for DbetaJbeta recombination. Instead, a promoter situated 5' to Dbeta1 (PDbeta) was required for efficient rearrangement of chromosomal substrates. A critical function for promoters in regulating gene segment accessibility was further supported by the ability of heterologous promoters to direct rearrangement of enhancer-containing substrates. Importantly, activation of a synthetic tetracycline-inducible promoter (Ptet) positioned upstream from the Dbeta gene segment was sufficient to target recombination of miniloci lacking a distal enhancer element. The latter result suggests that DNA loops, generated by interactions between flanking promoter and enhancer elements, are not required for efficient recognition of chromosomal gene segments by V(D)J recombinase. Unexpectedly, the Ptet substrate exhibited normal levels of rearrangement despite its retention of a hypermethylated DNA status within the DbetaJbeta cluster. Together, our findings support a model in which promoter activation, rather than intrinsic properties of enhancers, is the primary determinant for regulating recombinational accessibility within antigen receptor loci.

Citing Articles

DNA double-strand breaks relieve USF-mediated repression of Dβ2 germline transcription in developing thymocytes.

Stone J, McMillan R, Skaar D, Bradshaw J, Jirtle R, Sikes M J Immunol. 2012; 188(5):2266-75.

PMID: 22287717 PMC: 3288432. DOI: 10.4049/jimmunol.1002931.

The center of accessibility: Dβ control of V(D)J recombination.

Sikes M, McMillan R, Bradshaw J Arch Immunol Ther Exp (Warsz). 2010; 58(6):427-33.

PMID: 20890731 PMC: 3077077. DOI: 10.1007/s00005-010-0101-2.

Transcription-dependent mobilization of nucleosomes at accessible TCR gene segments in vivo.

Kondilis-Mangum H, Cobb R, Osipovich O, Srivatsan S, Oltz E, Krangel M J Immunol. 2010; 184(12):6970-7.

PMID: 20483751 PMC: 2909652. DOI: 10.4049/jimmunol.0903923.

TCR beta feedback signals inhibit the coupling of recombinationally accessible V beta 14 segments with DJ beta complexes.

Yang-Iott K, Carpenter A, Rowh M, Steinel N, Brady B, Hochedlinger K J Immunol. 2010; 184(3):1369-78.

PMID: 20042591 PMC: 2873682. DOI: 10.4049/jimmunol.0900723.

Promoter activity 5' of Dbeta2 is coordinated by E47, Runx1, and GATA-3.

McMillan R, Sikes M Mol Immunol. 2009; 46(15):3009-17.

PMID: 19592096 PMC: 2732994. DOI: 10.1016/j.molimm.2009.06.013.

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