Dataset Information

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.

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).

SUBMITTER: Convertini P

PROVIDER: S-EPMC6515469 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Convertini Paolo P Todisco Simona S De Santis Francesco F Pappalardo Ilaria I Iacobazzi Dominga D Castiglione Morelli Maria Antonietta MA Fondufe-Mittendorf Yvonne N YN Martelli Giuseppe G Palmieri Ferdinando F Infantino Vittoria V

International journal of molecular sciences 20190416 8

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 <i>SLC25A13</i> 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-aspar ...[more]

PMID: 30995827

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Project description:Mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) deficiency is an ultra-rare genetic disease characterized by global hypomyelination and brain atrophy, caused by mutations in the SLC25A12 gene leading to a reduction in AGC1 activity. In both neuronal precursor cells and oligodendrocytes precursor cells (NPCs and OPCs), the AGC1 determines reduced proliferation with an accelerated differentiation of OPCs, both associated with gene expression dysregulation. Epigenetic regulation of gene expression through histone acetylation plays a crucial role in the proliferation/differentiation of both NPCs and OPCs and is modulated by mitochondrial metabolism. In AGC1 deficiency models, both OPCs and NPCs show an altered expression of transcription factors involved in the proliferation/differentiation of brain precursor cells (BPCs) as well as a reduction in histone acetylation with a parallel alteration in the expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, histone acetylation dysfunctions have been dissected in in vitro models of AGC1 deficiency OPCs (Oli-Neu cells) and NPCs (neurospheres), in physiological conditions and following pharmacological treatments. The inhibition of HATs by curcumin arrests the proliferation of OPCs leading to their differentiation, while the inhibition of HDACs by suberanilohydroxamic acid (SAHA) has only a limited effect on proliferation, but it significantly stimulates the differentiation of OPCs. In NPCs, both treatments determine an alteration in the commitment toward glial cells. These data contribute to clarifying the molecular and epigenetic mechanisms regulating the proliferation/differentiation of OPCs and NPCs. This will help to identify potential targets for new therapeutic approaches that are able to increase the OPCs pool and to sustain their differentiation toward oligodendrocytes and to myelination/remyelination processes in AGC1 deficiency, as well as in other white matter neuropathologies.

Dataset Information

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.

Publications

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

Similar Datasets

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