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Vol. 17, No. 1, pp. 37-42, January 1, 2003
1 Department of Cell Biology, 2 Section of
Immunobiology, and 3 Howard Hughes Medical Institute, Yale
University School of Medicine, New Haven, Connecticut 06520-8011, USA;
4 Rosenstiel Basic Medical Research Center and Department
of Biology, Brandeis University, Waltham, Massachusetts 02454, USA
Pax5-deficient progenitor B (pro-B) cells are thought to
be severely defective for recombination of all immunoglobulin heavy chain (IgH) V gene segments, but the mechanism by which Pax5
regulates this process has not been defined. To address this issue, we
have examined the assembly of the IgH locus in Pax5-deficient
pro-B cells and find, unexpectedly, that 3' IgH V gene segments, which lie closest to the D-J-Cµ region, recombine efficiently, but
progressively more distal V gene segments recombine progressively less
efficiently. Histone acetylation and germ-line transcription correlate
strongly with an open or an accessible chromatin structure thought to
be permissive for V(D)J recombination, and defects in recombination are
typically accompanied by deficits in these processes. We were therefore
surprised to observe that distal VH gene segments in Pax5
/ pro-B cells exhibit no defect in these measures of
accessibility. The finding of transcribed, histone acetylated gene
segments that fail to recombine suggests that a Pax5-dependent
regulatory mechanism is required in addition to standard constraints of
accessibility to control VH gene recombination.
[Key Words: V(D)J recombination; Pax5; accessibility; lymphocyte development; locus control]
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