Elucidation of IgH intronic enhancer functions via germ-line deletion

AUTOR(ES)
FONTE

National Academy of Sciences

RESUMO

Studies of chimeric mice demonstrated that the core Ig heavy chain (IgH) intronic enhancer (iEμ) functions in V(D)J and class switch recombination at the IgH locus. To more fully evaluate the role of this element in these and other processes, we generated mice homozygous for germ-line mutations in which the core sequences of iEμ (cEμ) were either deleted (cEμΔ/Δ mice) or replaced with a pgk-NeoR cassette (cEμN/N mice). The cEμΔ/Δ mice had reduced B cell numbers, in association with impaired D to JH and VH to DJH rearrangement, whereas cEμN/N mice had a complete block in IgH V(D)JH recombination, confirming that additional cis elements cooperate with iEμ to enforce D to JH recombination. In addition, developing cEμΔ/Δ and cEμN/N B lineage cells had correspondingly decreased levels of germ-line transcripts from the JH region of the IgH locus (μ0 and Iμ transcripts); although both had normal levels of germ-line VH transcripts, suggesting that cEμ may influence IgH locus V(D)J recombination by influencing accessibility of JH proximal regions of the locus. Consistent with chimera studies, peripheral cEμΔ/Δ B cells had normal surface Ig and relatively normal class switch recombination. However, cEμΔ/Δ B cells also had relatively normal somatic hypermutation of their IgH variable region genes, showing unexpectedly that the cEμ is not required for this process. The availability of mice with the iEμ mutation in their germ line will facilitate future studies to elucidate the roles of iEμ in VH(D)JH recombination in the context of IgH chromatin structure and germ-line transcription.

ACESSO AO ARTIGO

Documentos Relacionados