Andrew Hoffman
VA Medical Center
Numerous studies have demonstrated the importance of DNA methylation as a mechanism underlying genomic imprinting. DNA that is rich in methylated CpGs is associated with hypoacetylated histone cores and increased histone H1, while DNA containing unmethylated CpG islands is associated with chromatin enriched in hyperacetylated histone cores and less histone H1. While the methylation of DNA may repress transcription by preventing the binding of transcription factors or by enhancing the binding of specific inhibitory proteins, it has also been shown dig DNA methylation generates an inactive DNase-resistant local chromatin structure with hypoacetylated core histories. The degree of core histone acetylation has been shown to modulate the expression of numerous genes. In general, histone deacetylation leads to transcriptional repression while histone acetylation increases gene transcription. Histone acetylation is maintained during mitosis, so the acetylation pattern represents a heritable epigenetic imprint which can influence gene transcription. Thus, the degree of histone acetylation may represent another potential mechanism which could initiate or maintain genomic imprinting.
We have recently shown that inhibition of histone deacetylation by trichostatin A (TSA) induces the expression of the normally imprinted 1gf2 allele, leading to biallelic expression of the gene in human and murine cells. When cultured cells are incubated with TSA, the differentially methylated region (DMR) 0 of 1gf2 becomes hypomethylated. Igf2r is an imprinted gene which is associated with a reciprocally imprinted antisense transcript. TSA treatment causes loss of Igf2r antisense imprinting, with little change in the expression of the imprinted sense Igf2r transcript. Moreover, TSA treatment is associated with a dose-dependent demethylation in the promoter region of Igf2r antisense; there were minimal changes in the methylation of the Igf2r sense promoter. Thus, the relaxation of imprinting seen in some genes after treatment with histone deacetylase inhibitors is associated with changes in DNA methylation in promoter regions or other relevant regions of the affected genes. Thus, in conjunction with DNA methylation, histone acetylation may represent a crucial molecular mechanism for initiating, maintaining and/or transmitting the genomic imprint.