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

Paolo Convertini, Simona Todisco, Francesco de Santis, Ilaria Pappalardo, Dominga Iacobazzi, Maria Antonietta Castiglione Morelli, Yvonne N Fondufe-Mittendorf, Giuseppe Martelli, Ferdinando Palmieri, Vittoria Infantino*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

8 Citations (Scopus)
173 Downloads (Pure)

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).
Original languageEnglish
Article number1888
Number of pages16
JournalInternational Journal of Molecular Sciences
Volume20
Issue number8
Early online date16 Apr 2019
DOIs
Publication statusPublished - 30 Apr 2019

Keywords

  • SLC25A13
  • AGC2
  • gene expression
  • transcriptional regulation
  • FOXA2
  • USF1

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