Regulation of T cell receptor gene assembly by local and long-range changes in chromatin accessibility
Oestreich, Kenneth Joseph
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2006-07-19
Abstract
Antigen receptor gene assembly is governed by transcriptional promoters and enhancers that communicate over large distances and modulate chromatin accessibility to V(D)J recombinase. The precise role of these cis-acting elements in opening chromatin at recombinase targets and the mechanisms underlying their collaboration remain unclear. I show that the TCR beta enhancer (Ebeta) directs long-range chromatin opening over both DbetaJbeta clusters. Strikingly, chromatin associated with the Dbeta1 gene segment is refractory to Ebeta-mediated opening. Accessibility at Dbeta1 is accompanied by the formation of a stable holocomplex between a Dbeta-proximal promoter, PDbeta1, and Ebeta. These findings indicate a stepwise process for DbetaJbeta recombination that relies on distinct aspects of Ebeta activity: an intrinsic function that directs general chromatin opening and a cooperative function with PDbeta1 that facilitates the unmasking of the Dbeta1 gene segment, triggering TCR beta gene assembly.