E2F6 (E2F transcription factor 6)

2004-03-01   Matthew Oberley 

McArdle Laboratory for Cancer Research, University of Wisconsin - Madison, 1400 University Ave. Madison, WI 53706, USA

Identity

HGNC
LOCATION
2p25.1
LOCUSID
ALIAS
E2F-6
FUSION GENES

DNA/RNA

Description

In humans, E2F6 has 8 exons that span 20881 bp of genomic sequence. It has an ORF of 843 nt.

Transcription

There have been 5 mRNA splice variants identified in humans.
  • Transcript variant 1 is the predominant transcript, and it encodes the longest mRNA isoform (a), which is 2342 bp.
  • Transcript variant 2 contains an additional segment (2413 bp mRNA), compared to variant 1, that causes a frameshift leading to an early stop codon. This transcript may function in a regulatory role with no protein translated. The predicted protein (isoform b) is much shorter than isoform a. Transcript variants 2 and 4 encode isoform b.
  • Transcript variant 3 lacks a segment (2287 bp mRNA), compared to variant 1, that causes a frameshift leading to an early stop codon. This transcript may function in a regulatory role with no protein translated. The predicted protein (isoform c) is much shorter than isoform a.
  • Transcript variant 4 contains two additional segments (2546 bp mRNA), compared to variant 1, that cause a frameshift leading to an early stop codon. This transcript may function in a regulatory role with no protein translated. The predicted protein (isoform b) is much shorter than isoform a.
  • Transcript variant 5 contains an additional segment (2475 bp mRNA), compared to variant 1, that causes a frameshift leading to an early stop codon. This transcript may function in a regulatory role with no protein translated. The predicted protein (isoform d) is much shorter than isoform a.
  • Pseudogene

    There is an E2F6 pseudogene located on chromosome 22q11.2 (LOC376818) containing 2144 bp of the E2F6 gene with no introns.

    Proteins

    Atlas Image
    Diagram created by M. Oberley.

    Description

    The predominately expressed isoform is 282 amino acids, and is . The DNA binding domain is thought to be between aa 50 and 129. It has a DEF box between aa 95 to 195. The dimerization domain is thought to reside between aa 130 and 222. There is a leucine zipper domain between aa 143 and 164. The transcriptional repression domain is located on the C terminus from aa 173 to 281. The N-terminal 1-75 aa are missing in isoform B which is predicted to be 206 AA.

    Expression

    Ubiquitous, though more highly expressed in the placenta, skeletal muscle, heart, ovary, kidney, small intestine and spleen.

    Localisation

    Nuclear

    Function

    Heterodimerization with DP1 or 2 creates a sequence specific transcriptional repressor. Overexpression of E2F6 can delay the exit of cells from S-phase, indicating a role for E2F6 in cell-cycle control. E2F6 has been shown via yeast two hybrid and co-IPs to interact with members of the polycomb repressive complex 1, such as Bmi1, RYBP, RING1, MEL-18, and Mph1. The functional outcome of these interactions are as of yet unclear. E2F6 has been biochemically purified in a complex containing polycomb group members h-1(3) mbt like protein, RING1, RING2, hMBLR, as well as YAF and HP1g; this complex also contained a novel euchromatic histone methyltransferase (Eu-HMTase1). This finding led to speculation that E2F6 controlled cellular entry into quiescence, but E2F6 nullizygous MEFs had no kinetic changes or defects in their ability to enter quiescence, or to re-enter into the cell-cycle. However, these animals had homeotic transformations of the axial skeleton, a phenotype that resembled Bmi1 nullizygous mice. This implicated E2F6 in regulation of normal development.

    Homology

    E2F6 has homology with E2Fs1-5 in the DNA-binding domain, the dimerization domain, and the marked box domain located between aa 231 and 239.

    Mutations

    Note

    A synthetic mutation in aa 68; L->E: reduced E2F6 transcriptional repressor activity by abrogating DNA binding, but had little effect on S-phase entry.

    Implicated in

    Entity name
    Development
    Note
    E2F6 is required for normal homeotic development in murine models as mice nullizygous for E2F6 display transformations in the axial skeleton.
    Disease
    None known.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    127711332003Dynamic recruitment of NF-Y and histone acetyltransferases on cell-cycle promoters.Caretti G et al
    97049271998E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription.Cartwright P et al
    123832622002Two different E2F6 proteins generated by alternative splicing and internal translation initiation.Dahme T et al
    96890561998Unusual proliferation arrest and transcriptional control properties of a newly discovered E2F family member, E2F-6.Gaubatz S et al
    115947472001Molecular cloning and characterization of the mouse E2F6 gene.Kherrouche Z et al
    94036821997An E2F-like repressor of transcription.Morkel M et al
    129096252003E2F6 negatively regulates BRCA1 in human cancer cells without methylation of histone H3 on lysine 9.Oberley MJ et al
    120041352002A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells.Ogawa H et al
    121011042002Homeotic transformations of the axial skeleton that accompany a targeted deletion of E2f6.Storre J et al
    118237942002Sibling rivalry in the E2F family.Trimarchi JM et al

    Other Information

    Locus ID:

    NCBI: 1876
    MIM: 602944
    HGNC: 3120
    Ensembl: ENSG00000169016

    Variants:

    dbSNP: 1876
    ClinVar: 1876
    TCGA: ENSG00000169016
    COSMIC: E2F6

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000169016ENST00000307236O75461
    ENSG00000169016ENST00000381525O75461
    ENSG00000169016ENST00000381525A0A0S2Z3K8
    ENSG00000169016ENST00000421117Q2Z196
    ENSG00000169016ENST00000428221F8WEZ5
    ENSG00000169016ENST00000437573F8WC40
    ENSG00000169016ENST00000444832Q2Z197
    ENSG00000169016ENST00000455198Q2Z197
    ENSG00000169016ENST00000542100O75461
    ENSG00000169016ENST00000542100Q53YM3
    ENSG00000169016ENST00000546212O75461
    ENSG00000169016ENST00000546212Q53YM3

    Expression (GTEx)

    0
    5
    10
    15
    20

    References

    Pubmed IDYearTitleCitations
    120041352002A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells.269
    179088212007A comprehensive ChIP-chip analysis of E2F1, E2F4, and E2F6 in normal and tumor cells reveals interchangeable roles of E2F family members.116
    241095972013Identification of cell cycle-regulated genes periodically expressed in U2OS cells and their regulation by FOXM1 and E2F transcription factors.73
    155360692005A novel repressive E2F6 complex containing the polycomb group protein, EPC1, that interacts with EZH2 in a proliferation-specific manner.56
    155745952004A role for E2F6 in distinguishing G1/S- and G2/M-specific transcription.44
    253193902014miR-185 suppresses tumor proliferation by directly targeting E2F6 and DNMT1 and indirectly upregulating BRCA1 in triple-negative breast cancer.44
    129096252003E2F6 negatively regulates BRCA1 in human cancer cells without methylation of histone H3 on lysine 9.32
    170013162007PHC3, a component of the hPRC-H complex, associates with E2F6 during G0 and is lost in osteosarcoma tumors.18
    197386112009Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis.17
    185626912008E2F6 inhibits cobalt chloride-mimetic hypoxia-induced apoptosis through E2F1.11

    Citation

    Matthew Oberley

    E2F6 (E2F transcription factor 6)

    Atlas Genet Cytogenet Oncol Haematol. 2004-03-01

    Online version: http://atlasgeneticsoncology.org/gene/521/e2f6