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 V H genes, when rearranged to D H J H genes, generates a diverse antibody repertoire. The V H locus encompasses 2.5 Mb, and rearrangement of V H genes in the D H -distal half of the locus are controlled very differently from the V H genes in the proximal end of the locus. The rearrangement of distal but not proximal V H 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 V H 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 V H segments and the repressive histone modification H3K27me3 is exclusively present on proximal V H segments. We observed an absence of H3K27me3 in fetal pro-B cells, which predominantly rearrange proximal V H 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 V H locus by differentially modulating two reciprocal histone modifications during B lymphocyte development.