Fine-tuning notes in the behavioral symphony: parent-of-origin allelic gene expression in the brain

Abstract

The gene encoding the thyroid hormone (TH)-metabolizing enzyme, deiodinase type III (Dio3), exhibits a preferential paternal expression in most tissues. Dio3 is part of the Dlk1-Dio3 imprinted locus, so named according to its ancestral genes, Delta-like homolog 1 (Dlk1) and Dio3, which among other important functions control metabolic programming in the developing embryo and fetus. Here, we describe the aspects of the genomic imprinting patterns exhibited by Dio3 across brain regions and development. The corresponding local changes in the dosage of the Dio3 enzyme are inversely related to TH levels that vary from one brain region to another, and affect social and cognitive behaviors. We show that this regional tuning of brain region-specific expression is dependent on parent of origin-specific genetic polymorphisms in the rat, is sexually dimorphic, and is affected by the early environmental challenge of fetal exposure to alcohol, opening the possibility that the potential for variant expression patterns of the Dio3 gene is quite large. The multiple regulatory genomic features within the Dlk1-Dio3 locus, and other imprinted loci, allow mammals to specifically modulate parent-of-origin allelic gene expression brain region. These regulatory structures seem to have evolved as a possible mechanism of adaptation in response to the simultaneous need for highly regulated expression in some tissues during development, but variable expression across specific regions of the brain over the complete life span. Here, we use Dio3 as a single gene example of the epigenetic parent-of-origin allelic expression in specific brain regions and discuss the potential of this general phenomenon to shape evolutionarily relevant social and cognitive behavior in eutherian mammals.

Keywords: Deiodinase-3; Genomic imprinting; Hippocampus; Neurodevelopment; Parent-of-origin; Thyroid hormone.