Chromatin remodeling by the T cell receptor (TCR)-β gene enhancer during early T cell development:: Implications for the control of TCR-β locus recombination

Gene targeting studies have shown that T cell receptor (TCR)-beta gene expression and recombination are inhibited after deletion of an enhancer (E beta) located at the 3' end of the similar to 500-kb TCR-beta locus. Using knockout mouse models, we have measured, at different regions throughout the TCR-beta locus, the effects of E beta deletion on molecular parameters believed to reflect epigenetic changes associated with the control of gene activation, including restriction endonuclease access to chromosomal DNA, germline transcription, DNA methylation, and histone H3 acetylation. Our results demonstrate that, in early developing thymocytes, E beta contributes to major chromatin remodeling directed to an similar to 25-kb upstream domain comprised of the DP-J beta locus regions. Accordingly, treatment of E beta-deleted thymocytes with the histone deacetylase inhibitor trichostatin A relieved the block in TCR-beta gene expression and promoted recombination within the DP-J beta loci- Unexpectedly, however, epigenetic processes at distal V beta genes on the 5' side of the locus and at the 3' proximal V beta 14 gene appear to be less dependent on E beta, suggesting that E beta activity is confined to a discrete region of the TCR-beta locus. These findings have implications with respect to the developmental control of TCR-beta gene recombination, and the process of allelic exclusion at this locus.