Hypothesis: the removal of VH gene downstream sequences is required for its expression in mature B cells.
In immunoglobulin producing cells only the rearranged VH gene is expressed, while all the other germline VH genes are silent. On the other hand, it was shown that unrearranged VH gene segments are expressed at a high level in the early stages of B lymphocyte differentiation. This expression is independent of the Ig heavy chain enhancer element. It seems, therefore, that unrearranged VH gene expression is depressed in mature B cells by a mechanism that will not operate on the rearranged functional heavy chain gene. We have shown that a highly conserved DNA segment is present upstream to several mouse and human VH genes. DNA sequencing downstream to germline genes revealed a DNA element related to the one described at the 5' of the VH genes. A model is proposed in which the 5' and 3' conserved segments are functional in the regulation of VH gene expression. The model suggests the existence of a protein in mature B cells which recognizes the 5' and 3' conserved DNA elements and prevents germline VH gene expression by binding to these segments. VH-D-JH joining results in the deletion of the 3' flanking sequences of the rearranged VH gene but not of other upstream VH genes. This would result in the release of promoter suppression in the case of the rearranged gene, while all other VH genes would remain transcriptionally silent.
Rechavi
G
G
Institute of Hematology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D001483:Base Sequence; D004247:DNA / Q000032:analysis; D005786:Gene Expression Regulation; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data
D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D004247:DNA