Contrasting Patterns in the Evolution of Vertebrate MLX Interacting Protein (MLXIP) and MLX Interacting Protein-Like (MLXIPL) Genes

Abstract

ChREBP and MondoA are glucose-sensitive transcription factors that regulate aspects of energy metabolism. Here we performed a phylogenomic analysis of Mlxip (encoding MondoA) and Mlxipl (encoding ChREBP) genes across vertebrates. Analysis of extant Mlxip and Mlxipl genes suggests that the most recent common ancestor of these genes was composed of 17 coding exons. Single copy genes encoding both ChREBP and MondoA, along with their interacting partner Mlx, were found in diverse vertebrate genomes, including fish that have experienced a genome duplication. This observation suggests that a single Mlx gene has been retained to maintain coordinate regulation of ChREBP and MondoA. The ChREBP-β isoform, the more potent and constitutively active isoform, appeared with the evolution of tetrapods and is absent from the Mlxipl genes of fish. Evaluation of the conservation of ChREBP and MondoA sequences demonstrate that MondoA is better conserved and potentially mediates more ancient function in glucose metabolism.

Sweet Sixteenth for ChREBP: Established Roles and Future Goals

“…Systematic serial deletions of the ChREBP sequence aiming to identify regions that confer glucose responsiveness led to the identification of an evolutionarily conserved domain located at the N terminus of Mondo proteins. This was named the glucose-sensing module (GSM), also known as mondo conserved region (MCR), composed of a low-glucose inhibitory domain (LID) and a transactivation domain called glucose-response activation conserved element (GRACE) (Singh and Irwin, 2016) (Li et al, 2006) (Figure 1). According to the LID/GRACE model, the glucose responsiveness of ChREBP is mediated by a dynamic intramolecular inhibition between LID and GRACE, in which low glucose concentrations restrain the transcriptional activity of GRACE through the LID, while high glucose releases this inhibition.…”

“…Second, many neurons do not take up glucose directly but instead are supplied with lactate from nearby glia and astrocytes (Teschemacher et al, 2015). Third, Drosophila Mio coded protein is also homologous to MondoA, a ubiquitous glucose-sensing homolog of ChREBP that could be another good candidate in regulating central glucose-responsive gene programs in mammals (Singh and Irwin, 2016). Therefore, further research would be necessary to define the physiological relevance of ChREBP in central glucose detection and metabolic regulation.…”

Carbohydrate Sensing Through the Transcription Factor ChREBP

“…Localization and transcriptional activation of ChREBP are determined by nutrient availability. Glucose-mediated regulation of ChREBP occurs mostly at the level of the glucose-sensing module (GSM) or mondo conserved region (MCR), which is composed of the LID and the GRACE domains, as mentioned in the introduction (Figure 1A>; Li et al, 2006; Singh and Irwin, 2016). In 2012, Herman et al (2012) described another ChREBP isoform, ChREBPβ, that is transcribed from an alternative first exon promoter 1b to exon 2 (Figure 1B>).…”

Influence of environmental conditions at spawning sites and migration routes on adaptive variation and population connectivity in Chinook salmon

“…The region on Chr10 contains several genes and the intergenic space. On Chr12 the SNPs are mostly located in intergenic regions, but also on a gene called MLX-interacting protein, a transcription activation protein (Singh & Irwin, 2016). The peak on Chr13 cor- In the analysis screening for putatively adaptive SNPs between summer-and fall-run fish, the largest association is again located on Chr28 in the GREB1L/ROCK1 region (Narum et al, 2018).…”