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(Ek et al., 2001; Muller et al., 2003). These polymorphic genes have also been found to be risk factors for obesity and diabetes in certain populations. In large-scale population studies that cut across regional energy environments, the associations with PPARγ and PGC-1α are lost (Diabetes Genetics Initiative of Broad Institute of Harvard and MIT et al., 2007; Scott et al., 2007; Sladek et al., 2007; Zeggini et al., 2007). This paradox may result from the mixing of populations from different energy environments which harbor alternative region-specific adaptive genetic variants, such that the impact of each individual regional variant is averaged out.

ENERGY FLUCTUATION AND CYCLIC ADAPTATION

Individual adjustments to cyclic changes in the energy environment must be reversible. Therefore, cyclic changes cannot be due to DNA sequence changes, but must be due to changes in bioenergetic gene expression. Relevant cyclic bioenergetic changes encompass a wide temporal range from intergenerational effects to daily fluctuations. The more long-term cyclic modulations occur as epigenomic changes at the chromatin level, whereas the shorter-term changes involve alterations of transcription factors, signal transduction pathways, and protein activation.

Epigenomic Regulation of Bioenergetics

Because the primary environmental variable is energetics, and because the bioenergetic genes are dispersed across the chromosomes and mtDNA, responses to environmental fluctuation must involve pan genomic regulation of bioenergetic genes. The modulation of the epigenome by intracellular concentrations of high-energy intermediates provides the necessary link between the energetic state of the environment and the modulation of cellular gene expression. When calories are abundant, the organism must grow and reproduce, which requires the up-regulation of gene expression. When calories are limiting, the organism must become quiescent, requiring the shutdown of gene expression (Wallace and Fan, 2010).

Epigenomic regulation occurs at the chromatin level. The nDNA is packaged in nucleosomes encompassing 146–147 base pairs of DNA wrapped around a complex of two copies each of histones H2A, H2B, H3, and H4. The amino-terminal tails of the histones are positively charged, such that they bind electrostatically to the phosphate backbone of the DNA and inhibit transcription. However, when the histone tails become phosphorylated by kinases using ATP, or acetylated by histone acetyl-transferases (HAT) using acetyl-CoA, the positive charges are neutralized, the affinity of the histone tails to DNA is reduced, and the chromatin opens to permit transcription. Methylation of DNA and of histone tails by



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