Pappalardo, X. G. | Search bioRxiv

bioRxiv2023

Human VDAC pseudogenes: an emerging role for VDAC1P8 pseudogene in acute myeloid leukemia

BackgroundVoltage-dependent anion selective channels (VDACs) are the most abundant mitochondrial outer membrane proteins, encoded in mammals by three genes, VDAC1, 2 and 3, mostly ubiquitously expressed. As mitochondrial gatekeepers, VDACs control organelle and cell metabolism and are involved in many diseases. Despite the presence of numerous VDAC pseudogenes in the human genome, their significance and possible role in VDAC protein expression has not yet been considered. ResultsWe investigated the relevance of processed pseudogenes of human VDAC genes, both in physiological and in pathological contexts. Using high-throughput tools and querying many genomic and transcriptomic databases, we show that some VDAC pseudogenes are transcribed in specific tissues and pathological contexts. The obtained experimental data confirm an association of the VDAC1P8 pseudogene with acute myeloid leukemia (AML). ConclusionsOur in-silico comparative analysis between the VDAC1 gene and its VDAC1P8 pseudogene, together with experimental data produced in AML cellular models, indicate a specific over-expression of the VDAC1P8 pseudogene in AML, correlated with a downregulation of the parental VDAC1 gene.

genomics↗

bioRxiv2020

The secret of VDAC isoforms is in their gene regulation? Characterization of human VDAC genes expression profile, promoter activity, and transcriptional regulators.

BackgroundVDACs (Voltage-Dependent Anion-selective Channels) are pore-forming proteins of the outer mitochondrial membrane, whose permeability is primarily due to their presence. In higher eukaryotes three isoforms 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. ResultsVDAC isoforms are broadly but also specifically expressed in various human tissues at different levels with a predominance of VDAC1 and VDAC2 over VDAC3. However, RNA-seq 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 was investigated. The main regulators common to the three VDAC genes were identified as E2FF, NRF1, KLFS, EBOX transcription factors family members. All of them are involved in cell cycle and growth, proliferation, differentiation, apoptosis, and metabolism. More transcription factors specific for each isoform gene were identified, supporting the results in the literature, indicating a general role of VDAC1, as actor of apoptosis for VDAC2, and the involvement in sex determination and development of VDAC3. ConclusionsFor 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 VDAC protein family in mitochondrial functionality. Moreover, insights about a specialized function and different regulation mechanisms arise for the three isoforms genes.

molecular biology↗