Transcriptional Regulation Factors of the Human Mitochondrial Aspartate/Glutamate Carrier Gene, Isoform 2 ( SLC25A13): USF1 as Basal Factor and FOXA2 as Activator in Liver Cells

Int J Mol Sci. 2019 Apr 16;20(8):1888. doi: 10.3390/ijms20081888.

Abstract

Mitochondrial carriers catalyse the translocation of numerous metabolites across the inner mitochondrial membrane, playing a key role in different cell functions. For this reason, mitochondrial carrier gene expression needs tight regulation. The human SLC25A13 gene, encoding for the mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), catalyses the electrogenic exchange of aspartate for glutamate plus a proton, thus taking part in many metabolic processes including the malate-aspartate shuttle. By the luciferase (LUC) activity of promoter deletion constructs we identified the putative promoter region, comprising the proximal promoter (-442 bp/-19 bp), as well as an enhancer region (-968 bp/-768 bp). Furthermore, with different approaches, such as in silico promoter analysis, gene silencing and chromatin immunoprecipitation, we identified two transcription factors responsible for SLC25A13 transcriptional regulation: FOXA2 and USF1. USF1 acts as a positive transcription factor which binds to the basal promoter thus ensuring SLC25A13 gene expression in a wide range of tissues. The role of FOXA2 is different, working as an activator in hepatic cells. As a tumour suppressor, FOXA2 could be responsible for SLC25A13 high expression levels in liver and its downregulation in hepatocellular carcinoma (HCC).

Keywords: AGC2; FOXA2; SLC25A13; USF1; gene expression; transcriptional regulation.

MeSH terms

  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Hep G2 Cells
  • Hepatocyte Nuclear Factor 3-beta / metabolism*
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Mitochondrial Membrane Transport Proteins / genetics*
  • Promoter Regions, Genetic
  • Transcriptional Activation*
  • Upstream Stimulatory Factors / metabolism*

Substances

  • FOXA2 protein, human
  • Mitochondrial Membrane Transport Proteins
  • SLC25A13 protein, human
  • USF1 protein, human
  • Upstream Stimulatory Factors
  • Hepatocyte Nuclear Factor 3-beta