Abstract
Murine
Tcrd
and
Tcra
gene segments reside in a single genetic locus and undergo recombination in CD4
−
CD8
−
(double negative [DN]) and CD4
+
CD8
+
(double positive [DP]) thymocytes, respectively.
TcraTcrd
locus variable gene segments are subject to complex regulation. Only a small subset of ∼100 variable gene segments contributes substantially to the adult TCR
δ
repertoire. Moreover, although most contribute to the TCR
α
repertoire, variable gene segments that are J
α
proximal are preferentially used during primary
Tcra
recombination. We investigate the role of local chromatin accessibility in determining the developmental pattern of
TcraTcrd
locus variable gene segment recombination. We find variable gene segments to be heterogeneous with respect to acetylation of histones H3 and H4. Those that dominate the adult TCR
δ
repertoire are hyperacetylated in DN thymocytes, independent of their position in the locus. Moreover, proximal variable gene segments show dramatic increases in histone acetylation and germline transcription in DP thymocytes, a result of super long-distance regulation by the
Tcra
enhancer. Our results imply that differences in chromatin accessibility contribute to biases in
TcraTcrd
locus variable gene segment recombination in DN and DP thymocytes and extend the distance over which the
Tcra
enhancer can regulate chromatin structure to a remarkable 525 kb.