Regulation of TCRβ Gene Assembly by a Promoter/Enhancer Holocomplex

SummaryAntigen 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 crosstalk remain unclear. We show that the TCRβ enhancer (Eβ) directs long-range chromatin opening over both DβJβ clusters. Strikingly, chromatin associated with the Dβ1 gene segment is refractory to Eβ-mediated opening. Accessibility at Dβ1 is accompanied by the formation of a stable holocomplex between a Dβ-proximal promoter and Eβ. These findings indicate a stepwise process for Dβ → Jβ recombination that relies on distinct aspects of Eβ activity: an intrinsic function that directs general chromatin opening and a cooperative function that facilitates the assembly of a promoter/enhancer holocomplex, unmasks the Dβ1 gene segment, and triggers TCRβ gene assembly.