Histone acetylation determines the developmentally regulated accessibilityfor T cell receptor gamma gene recombination

Variable/diversity/joining (V[D]J) recombination of the T cell receptor (TC R) and immunoglobulin (Ig) genes is regulated by chromatin accessibility of the target locus to the recombinase in a lineage- and stage-specific manne r. Histone acetylation has recently been proposed as a molecular mechanism underlying the accessibility control. Here, we investigate the role for his tone acetylation in the developmentally regulated rearrangements of the mou se TCR-gamma gene, wherein predominant rearrangement is switched from V gam ma3 to V gamma2 gene during the fetal to adult thymocyte development. Our r esults indicate that histone acetylation correlates with accessibility, as histone acetylation at the fetal-type V gamma3 gene in accord with germline transcription is relatively high in fetal thymocytes, but specifically bec omes low in adult thymocytes within the entirely hyperacetylated locus. Fur thermore, inhibition of histone deacetylation during the development of adu lt bone marrow-derived thymocytes by a specific histone deacetylase inhibit or, trichostatin A, leads to elevated histone acetylation, germline transcr iption, cleavage, and rearrangement of the V gamma3 gene. These data demons trate that histone acetylation functionally determines the chromatin access ibility for V(D)J recombination in vivo and that an epigenetic modification of chromatin plays a direct role in executing a developmental switch in ce ll fate determination.