Tissue-specific imprinting of the G protein Gs is associated with tissue-specific differences in histone methylation

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Abstract
The G protein G s α is imprinted in a tissue-specific manner, being primarily expressed from the maternal allele in some tissues, such as renal proximal tubules. The G s α promoter is unmethylated, but is downstream of a differentially methylated region [the exon 1A differentially methylated region (DMR)] that is methylated on the maternal allele. Maternal G s α null mutations or loss of maternal-specific exon 1A methylation leads to pseudohypoparathyroidism types 1A or 1B, respectively. We now have examined the chromatin state of each parental allele within the exon 1A-G s α promoter region by chromatin immunoprecipitation of samples derived from mice with heterozygous deletions within the region using antibodies to covalently modified histones. The exon 1A DMR had allele-specific differences in histone acetylation and methylation, with histone acetylation and H3 lysine 4 (H3K4) methylation of the paternal allele, and H3 lysine 9 (H3K9) methylation of the maternal allele. Both parental alleles had similar levels of histone acetylation and H3K4 methylation within the G s α promoter and first exon, with no H3K9 methylation. In liver, where G s α is biallelically expressed, both parental alleles had similar levels of tri- and dimethylated H3K4 within the G s α first exon. In contrast, in renal proximal tubules there was a greater ratio of tri- to dimethylated H3K4 of G s α exon 1 in the more transcriptionally active maternal as compared with the paternal allele. These results show that allele-specific differences in G s α expression correlate in a tissue-specific manner with allele-specific differences in the extent of H3K4 methylation, and are the first demonstration that chronic transcriptional activation in mammals is correlated with trimethylation of H3K4.

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