Abstract
Uncoupling protein 1 (UCP1) permits non-shivering thermogenesis (NST) when highly expressed in brown adipose tissue (BAT) mitochondria. Exclusive to placental mammals, BAT has commonly been regarded to be advantageous for thermoregulation in hibernators, small-bodied species, and the neonates of larger species. While numerous regulatory control motifs associated with UCP1 transcription have been proposed for murid rodents, it remains unclear whether these are conserved across the eutherian mammal phylogeny and hence essential for UCP1 expression. To address this shortcoming, we conducted a broad comparative survey of putative UCP1 transcriptional regulatory elements in 139 mammals (135 eutherians). We find no evidence for presence of a UCP1 enhancer in monotremes and marsupials, supporting the hypothesis that this control region evolved in a stem eutherian ancestor. We additionally reveal that several putative promoter elements (e.g., CRE-4, CCAAT) identified in murid rodents are not conserved among BAT-expressing eutherians, and together with the putative regulatory region (PRR) and CpG island do not appear to be crucial for UCP1 expression. The specificity and importance of the upTRE, dnTRE, URE1, CRE-2, RARE-2, NBRE, BRE-1, and BRE-2 enhancer elements first described from rats and mice are moreover uncertain as these motifs differ substantially—but generally remain highly conserved—in other BAT-expressing eutherians. Other UCP1 enhancer motifs (CRE-3, PPRE, and RARE-3) as well as the TATA box are also highly conserved in nearly all eutherian lineages with an intact UCP1. While these transcriptional regulatory motifs are generally also maintained in species where this gene is pseudogenized, the loss or degeneration of key basal promoter (e.g., TATA box) and enhancer elements in other UCP1-lacking lineages make it unlikely that the enhancer region is pleiotropic (i.e., co-regulates additional genes). Importantly, differential losses of (or mutations within) putative regulatory elements among the eutherian lineages with an intact UCP1 suggests that the transcriptional control of gene expression is not highly conserved in this mammalian clade.
Highlights
Uncoupling protein 1 (UCP1) expression is a defining characteristic of brown adipose tissue (BAT), allowing this specialized eutherian heater organ to function in non-shivering thermogenesis (NST)
The predicted platypus UCP1 CDS available on GenBank is unique in that it creates a hypothetical open reading frame composed of seven exons; the usual 126 bp exon 1 is divided into two separate exons of 30 and 120 bp in length
Our results demonstrate that the CpG island and putative regulatory region (PRR) are not universally conserved among BAT-expressing eutherians and are likely not required for UCP1 transcription
Summary
Uncoupling protein 1 (UCP1) expression is a defining characteristic of brown adipose tissue (BAT), allowing this specialized eutherian heater organ to function in non-shivering thermogenesis (NST). BAT is highly vascularized and localized primarily to the thoracic region, lying adjacent to major blood vessels of the heart (e.g., the Sulzer’s vein) permitting effective transfer of NST heat to the rest of the body via the circulatory system (Klingenspor and Fromme, 2012; Oelkrug et al, 2015) This provides a more efficient means of heat production than shivering thermogenesis, which has major drawbacks as it impedes locomotion and produces heat in large muscle groups of the limbs that are prone to heat loss due to their high surface area to volume ratios (Oelkrug et al, 2015). UCP1 is widely considered to have provided a key thermoregulatory and evolutionary advantage to the eutherian lineage, for small-bodied and hibernating species, and, while BAT in largerbodied species (e.g., humans) is typically lost with the onset of adulthood, it has been generally understood to play vital role in their neonates (Cannon and Nedergaard, 2004)
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