Reciprocal patterns of methylation of H3K36 and H3K27 on proximal vs. distal IgVH genes are modulated by IL-7 and Pax5.

The usage of >100 functional murine Ig heavy chain VH genes, when rearranged to DHJH genes, generates a diverse antibody repertoire. The VH locus encompasses 2.5 Mb, and rearrangement of VH genes in the DH-distal half of the locus are controlled very differently from the VH genes in the proximal end of the locus. The rearrangement of distal but not proximal VH genes is impaired in mice deficient in the cytokine IL-7 or its receptor, in the transcription factor Pax5. or in Ezh2, a histone methyltransferase for Lys-27 of histone H3 (H3K27). The relative role of IL-7, Pax5, and Ezh2 in regulating distal vs. proximal VH rearrangement is not clear. Here, we show by ChIP and ChIP-on-chip that the active histone modification H3K36me2 is most highly associated with distal VH segments and the repressive histone modification H3K27me3 is exclusively present on proximal VH segments. We observed an absence of H3K27me3 in fetal pro-B cells, which predominantly rearrange proximal VH genes. Absence of IL-7 signaling reduces H3K36me2, and overexpression of IL-7 increases H3K36me2. In contrast, the major effect of the absence of Pax5 is the reduction in H3K27me3. Our data indicate that the cytokine IL-7 and the transcription factor Pax5 influence the rearrangement of the two regions of the VH locus by differentially modulating two reciprocal histone modifications during B lymphocyte development. [ABSTRACT FROM AUTHOR]