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Gene
Rearrangement by CBF/PEBP2
By
From the Department of Immunology, Duke University Medical Center, Durham, North
Carolina 27710
We have analyzed transgenic mice carrying versions of a human T cell receptor (TCR)-
gene
minilocus to study the developmental control of VDJ (variable/diversity/joining) recombination. Previous data indicated that a 1.4-kb DNA fragment carrying the TCR- enhancer (E
)
efficiently activates minilocus VDJ recombination in vivo. We tested whether the transcription
factor CBF/PEBP2 plays an important role in the ability of E to activate VDJ recombination by analyzing VDJ recombination in mice carrying a minilocus in which the E3 element of E
includes a mutated CBF/PEBP2 binding site. The enhancer-dependent VD to J step of minilocus rearrangement was dramatically inhibited in three of four transgenic lines, arguing that the
binding of CBF/PEBP2 plays a role in modulating local accessibility to the VDJ recombinase in
vivo. Because mutation of the E3 binding site for the transcription factor c-Myb had previously established a similar role for c-Myb, and because a 60-bp fragment of E carrying E3 and
E4 binding sites for CBF/PEBP2, c-Myb, and GATA-3 displays significant enhancer activity
in transient transfection experiments, we tested whether this fragment of E is sufficient to activate VDJ recombination in vivo. This fragment failed to efficiently activate the enhancerdependent VD to J step of minilocus rearrangement in all three transgenic lines examined, indicating that the binding of CBF/PEBP2 and c-Myb to their cognate sites within E, although
necessary, is not sufficient for the activation of VDJ recombination by E. These results imply
that CBF/PEBP2 and c-Myb collaborate with additional factors that bind elsewhere within E
to modulate local accessibility to the VDJ recombinase in vivo.
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