An Alternative Promoter in the Mouse Major Histocompatibility Complex Class II I-Aβ Gene: Implications for the Origin of CpG Islands

ABSTRACT

Nonmethylated CpG islands are generally located at the 5′ ends of genes, but a CpG island in the mouse major histocompatibility complex class II I-Aβ gene is remote from the promoter and covers exon 2. We have found that this CpG island includes a novel intronic promoter that is active in embryonic and germ cells. The resulting transcript potentially encodes a severely truncated protein which would lack the signal peptide and external β₁ domains. The functional significance of the internal CpG island may be to facilitate gene conversion, thereby sustaining the high level of polymorphism seen at exon 2. Deletions of the I-Aβ CpG island promoter reduce transcription and frequently lead to methylation of the CpG island in a transgenic mouse assay. These and other results support the idea that all CpG islands arise at promoters that are active in early embryonic cells.

ACKNOWLEDGMENTS

We thank Deborah Fowlis for tutoring in the production of transgenic animals, Susan Carson for the MHC clones, Austin Smith for the BALB/c ES cells, and Aileen Greig, Joan Davidson, and the staff of the Ann Walker Building for technical support. We also thank our photographic department for help in producing the figures and Brian Hendrich for helpful comments on the manuscript.

This work was supported by The Welcome Trust and The Howard Hughes Medical Institute.