Abstract
VDACs (voltage-dependent anion-selective channels) are pore-forming proteins of the outer mitochondrial membrane, whose permeability is primarily due to VDACs’ presence. In higher eukaryotes, three isoforms are raised during the evolution: they have the same exon–intron organization, and the proteins show the same channel-forming activity. We provide a comprehensive analysis of the three human VDAC genes (VDAC1–3), their expression profiles, promoter activity, and potential transcriptional regulators. VDAC isoforms are broadly but also specifically expressed in various human tissues at different levels, with a predominance of VDAC1 and VDAC2 over VDAC3. However, an RNA-seq cap analysis gene expression (CAGE) approach revealed a higher level of transcription activation of VDAC3 gene. We experimentally confirmed this information by reporter assay of VDACs promoter activity. Transcription factor binding sites (TFBSs) distribution in the promoters were investigated. The main regulators common to the three VDAC genes were identified as E2F-myc activator/cell cycle (E2FF), Nuclear respiratory factor 1 (NRF1), Krueppel-like transcription factors (KLFS), E-box binding factors (EBOX) transcription factor family members. All of them are involved in cell cycle and growth, proliferation, differentiation, apoptosis, and metabolism. More transcription factors specific for each VDAC gene isoform were identified, supporting the results in the literature, indicating a general role of VDAC1, as an actor of apoptosis for VDAC2, and the involvement in sex determination and development of VDAC3. For the first time, we propose a comparative analysis of human VDAC promoters to investigate their specific biological functions. Bioinformatics and experimental results confirm the essential role of the VDAC protein family in mitochondrial functionality. Moreover, insights about a specialized function and different regulation mechanisms arise for the three isoform gene.
Highlights
The VDAC is the prototype of the family of subcellular pores responsible for the permeability of the mitochondrial outer membrane [1]
We provide a comprehensive analysis of the three human VDAC genes (VDAC1–3), their expression profiles, promoter activity, and potential transcriptional regulators
The vast amount of large-scale genomic projects, high-throughput sequencing, and transcriptomic data, as well as the plentiful supply of promoter resources, assist in the comprehensive reconstruction of a transcriptional regulatory region. The intersection of this data enabled us to provide a framework of the main functional DNA elements for the identification of active biochemical regions, which are commonly understood as gene promoter sequences of each VDAC isoform, and to study the transcriptional control of the promoter structure via the analysis of TF-binding sites specificity and co-association patterns with other TFs
Summary
The VDAC (voltage-dependent anion-selective channel) is the prototype of the family of subcellular pores responsible for the permeability of the mitochondrial outer membrane [1]. This protein is a key control point for the passage of ions and metabolites and guarantees cell energy production. The three VDAC genes codify proteins with apparently the same function, differences in their amino acid content, the mitochondrial outer membrane localization [9], the channel functionality and voltage dependence [6,7], and the contribution of the N-terminal portion to cell viability and survival [10], lead to the hypothesis of a more specialized role/function for each isoform in different biological contexts
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