Comparative Analysis of Insulin Gene Promoters: Implications for Diabetes Research

Colin W. Hay; Kevin Docherty

Disclosures

Diabetes. 2006;55(12):3201-3213. 

In This Article

Effects Of Chromatin Structure

Efficient transcription is the outcome of coordinated dynamic arrangements upon the promoter. ChIP assays using MIN6 ß-cells have shown that PDX-1, MafA, E47, and ß2 bind to the mouse insulin 2 promoter in a cyclical manner with a periodicity of ~10–15 min.[125] Insulin gene regulation is also influenced by epigenic factors that include DNA methylation and alterations in histone modifications, which affect the packaging of DNA within chromatin. There are a number of studies on the role of histone acetylation and methylation in the control of insulin gene expression. A key role for histone acetyl transferase (HAT) p300 in insulin promoter regulation has been demonstrated by the observations that PDX-1 and ß2 mediate their effects on the rat insulin 2 gene through an interaction with p300,[31,126,127] while activation of a rat insulin 1 promoter construct in HeLa cells by PDX-1 requires interactions with p300.[128] It has also been shown that the effects of glucose on a rat insulin 1 promoter construct in the mouse MIN6 ß-cell line involved the recruitment by PDX-1 of HAT and histone deacetylase activities (HDAC) activities. Thus, under low-glucose conditions, PDX-1 associated with HDACs to repress transcription,[129] whereas under high glucose conditions PDX-1 recruited the HAT p300 to activate transcription.[130] PDX-1 has also been linked to the presence of methylated histone H3, i.e., H3K4me (nomenclature as per[131]), at the proximal promoter and coding regions of the insulin gene in rodent cells.[132] More recently, the histone methyl transferase set9 has been localized to ß-cells in association with the insulin gene.[133]

Investigations into the role of chromatin accessibility in insulin expression have revealed that PDX-1 shows preferential binding to open chromatin (euchromatin) over condensed chromatin (heterochromatin). In particular, PDX-1 occupies the endogenous insulin promoter in mouse ßTC3 ß-cells but not in mPAC ductal cells, which do not express insulin. Furthermore, the binding affinity of PDX-1 is strongly influenced by the position of nucleosomes relative to its regulatory element.[134] Even within euchromatin, the degree of openness varies as the A3/A4 region (–126 to –296) to which PDX-1 can bind contained the most open chromatin structure based on micrococcal nuclease digestion, whereas the adjacent region (–297 to –460), which is not as crucial for ß-cell–specific insulin transcription, was more condensed. Although it is likely that the insulin gene is embedded in euchromatin in ß-cells and in more condensed heterochromatin in non-ß-cells, it may be of relevance that the synteny studies (see INSULIN GENES) show that the human insulin gene lies only 2 kbp from the transcriptionally active TH gene, whereas this distance is >100-fold greater in rodents. Thus, the diverse efforts to induce insulin expression in non-ß-cells may be less problematic in humans than in rodents.

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