Sleeping Beauty, Awake! Regulation of Insulin Gene Expression by Methylation of Histone H3

In all cell types of the body, save one, the insulin gene is quiescent and is ensconced in a compact and protected environment of chromatin. How the insulin gene is coaxed out of its chromatin slumber in the pancreatic β-cell is unknown. Moreover, this question is of practical concern to current efforts to transform stems cells or other cells types to become insulin-secreting cells as means for treating type 1 diabetes. The DNA of all eukaryotic organisms including humans is wrapped around an octamer of the histone proteins H2A, H2B, H3, and H4 and garnished with a large array of proteins that collectively orchestrate the higher-order packaging, DNA replication, chromosomal division and recombination, and gene transcription. In recent years, molecular biologists have discovered that an essential step of teasing a gene out of dormancy is to modify the histones that lie in direct contact with the regulatory regions of genes. The two most important enzymatic histone modifications in this process are acetylation and methylation (1–3), which act together to open the chromatin structure and allow access of the promoter regions of genes to RNA polymerase and other transcription factors. Methylation of a specific lysine residue (Lys4) in the H3 histone (H3K4) is the most common modification in the gene promoter region of “poised” or actively transcribing genes (4,5). The methylation of H3K4 can vary between one to three methyl groups being added to this …