PMID- 33036380
OWN - NLM
STAT- MEDLINE
DCOM- 20210301
LR  - 20210301
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 19
DP  - 2020 Oct 7
TI  - Is the secret of VDAC Isoforms in their gene regulation? Characterization of 
      human VDAC genes expression profile, promoter activity, and transcriptional 
      regulators.
LID - 10.3390/ijms21197388 [doi]
LID - 7388
AB  - 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.
FAU - Zinghirino, Federica
AU  - Zinghirino F
AUID- ORCID: 0000-0001-8822-4217
AD  - Department of Biomedical and Biotechnological Sciences, University of Catania, 
      Via S. Sofia 64, 95123 Catania, Italy.
FAU - Pappalardo, Xena Giada
AU  - Pappalardo XG
AD  - Department of Biomedical and Biotechnological Sciences, University of Catania, 
      Via S. Sofia 64, 95123 Catania, Italy.
FAU - Messina, Angela
AU  - Messina A
AD  - Department of Biological, Geological and Environmental Sciences, Section of 
      Molecular Biology, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
AD  - National Institute for Biostructures and Biosystems, Section of Catania, 00136 
      Rome, Italy.
AD  - We.MitoBiotech S.R.L., c.so Italia 172, 95129 Catania, Italy.
FAU - Guarino, Francesca
AU  - Guarino F
AUID- ORCID: 0000-0002-0704-7333
AD  - Department of Biomedical and Biotechnological Sciences, University of Catania, 
      Via S. Sofia 64, 95123 Catania, Italy.
AD  - National Institute for Biostructures and Biosystems, Section of Catania, 00136 
      Rome, Italy.
AD  - We.MitoBiotech S.R.L., c.so Italia 172, 95129 Catania, Italy.
FAU - De Pinto, Vito
AU  - De Pinto V
AUID- ORCID: 0000-0001-5513-2906
AD  - Department of Biomedical and Biotechnological Sciences, University of Catania, 
      Via S. Sofia 64, 95123 Catania, Italy.
AD  - National Institute for Biostructures and Biosystems, Section of Catania, 00136 
      Rome, Italy.
AD  - We.MitoBiotech S.R.L., c.so Italia 172, 95129 Catania, Italy.
LA  - eng
PT  - Journal Article
DEP - 20201007
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (Transcription Factors)
RN  - 0 (Voltage-Dependent Anion Channels)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Binding Sites
MH  - Cell Line, Tumor
MH  - Computational Biology/methods
MH  - Databases, Genetic
MH  - Gene Expression Profiling
MH  - *Gene Expression Regulation
MH  - HeLa Cells
MH  - Humans
MH  - Mitochondrial Proteins/genetics/metabolism
MH  - Multigene Family
MH  - Nucleotide Motifs
MH  - Promoter Regions, Genetic
MH  - Protein Isoforms
MH  - Transcription Factors/metabolism
MH  - Transcriptional Activation
MH  - Voltage-Dependent Anion Channels/*genetics/metabolism
PMC - PMC7582299
OTO - NOTNLM
OT  - VDAC isoforms
OT  - core promoter
OT  - expression profile
OT  - gene structure
OT  - mitochondrial function
OT  - transcription factor binding sites
COIS- The authors declare no conflict of interest.
EDAT- 2020/10/11 06:00
MHDA- 2021/03/02 06:00
PMCR- 2020/10/01
CRDT- 2020/10/10 01:02
PHST- 2020/09/08 00:00 [received]
PHST- 2020/10/02 00:00 [revised]
PHST- 2020/10/03 00:00 [accepted]
PHST- 2020/10/10 01:02 [entrez]
PHST- 2020/10/11 06:00 [pubmed]
PHST- 2021/03/02 06:00 [medline]
PHST- 2020/10/01 00:00 [pmc-release]
AID - ijms21197388 [pii]
AID - ijms-21-07388 [pii]
AID - 10.3390/ijms21197388 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Oct 7;21(19):7388. doi: 10.3390/ijms21197388.