Alternative titles; symbols
HGNC Approved Gene Symbol: CBFA2T2
Cytogenetic location: 20q11.21-q11.22 Genomic coordinates (GRCh38) : 20:33,490,096-33,650,030 (from NCBI)
CBFA2T2 belongs to a family of ubiquitously expressed transcriptional repressors that interact with transcription factors bound to promoters of target genes and with histone deacetylases (HDACs; see 601241) critical for enforcement of repressor function (summary by Kumar et al., 2008).
To identify potential new genes homologous to ETO (133435), Fracchiolla et al. (1998) screened the EST database using the entire ETO cDNA sequence as a probe. Among the ESTs identified, they selected 2 overlapping clones and sequenced them to completion. A putative translation initiation site was identified by the presence of a strong Kozak consensus sequence, followed by a 1,725-bp open reading frame coding for a putative protein of 575 amino acids. They named this gene EHT for 'ETO homolog on chromosome twenty.' The putative EHT protein is approximately 65% identical to ETO/MTG8 (RUNX1T1; 133435) and approximately 24% identical to an ETO Drosophila homolog, Nervy. Northern blot analysis detected variable expression of EHT transcripts of about 7.5 and 9.5 kb in all tissues examined. Expression was highest in adult heart, skeletal muscle, and brain and in fetal brain and kidney.
Calabi and Cilli (1998) cloned 2 splice variants of CBFA2T2, which they called MTGR1, from human retina and MOLT1 T cells. The variants differ in their use of alternative 5-prime exons and encode proteins of 575 and 595 amino acids that differ at their N termini. Northern blot analysis of mouse tissues detected Mtgr1 expression in all tissues examined, with highest expression in brain. Expression was also detected in mouse embryos at day 16. Nuclease protection experiments showed MTGR1 expression in human thymus and hematopoietic cell lines. Northern blot analysis detected major MTGR1 transcripts of about 7.5 and 6 kb and minor transcripts of about 3 and 1.5 kb in human hemopoietic tissues. The major mRNAs were present at higher levels in lymphoid organs than in myeloid lineages. Calabi and Cilli (1998) determined that there are at least 2 MTGR1 homologs in the mouse genome, one of which shows features of a retroposon.
By 5-prime RACE of K562 cells, mammary gland, pancreas, and liver cDNA, Morohoshi et al. (2000) cloned 2 splice variants of MTGR1. MTGR1A, which includes exon 3 and uses a start codon in exon 4, encodes a deduced 575-amino acid protein. MTGR1B, which lacks exon 3 and uses a start codon in exon 2, encodes a deduced 604-amino acid protein. Northern blot analysis detected transcripts of 7.5 and 9.3 kb in all adult and fetal human tissues examined, with highest expression in adult thymus, prostate, spleen, and lymph node. The 7.5-kb transcript was detected in all human cell lines examined.
Kitabayashi et al. (1998) identified EHT as MTGR1 (myeloid translocation gene-related protein-1), a protein that interacts with the AML1 (151385)-MTG8 fusion protein. Their data suggested the presence of 2 alternative 5-prime ends of the MTGR1/EHT gene. Cytogenetic studies had shown that the 20q11 region is deleted in approximately 10% of cases of polycythemia vera, approximately 5% of cases of myelodysplastic syndromes, and approximately 3% of cases of acute myeloid leukemias. Kitabayashi et al. (1998) showed the direct interaction of MTGR1 in the AML1-MTG8 fusion protein, leading to an enhancement of cell proliferation mediated by granulocyte colony-stimulating factor (CSF3; 138970) in a murine myeloid model. This suggested that MTGR1 has an oncogenic rather than a tumor suppressor activity. Nevertheless, when MTGR1 was transfected alone into the same murine myeloid model cell line, the proliferative response to CSF was lower than that in the normal control, thus suggesting a possible negative growth control in normal cells.
Moore et al. (2008) showed that epitope-tagged mammalian Mtgr1, Mtg8, and Mtg16 (CBFA2T3; 603870) interacted with human TCF4 (TCF7L2; 602228) in cotransfected COS-7 cells. The Wnt signaling protein beta-catenin (CTNNB1; 116806) disrupted interaction of Mtg proteins with TCF4. When expressed in Xenopus embryos, Mtg family members inhibited Wnt-dependent axis formation and impaired the ability of beta-catenin or Lef1 (153245) to induce axis duplication. Furthermore, Myc (190080), a transcriptional target of the Wnt pathway, was overexpressed in the small intestine of mice lacking Mtgr1. Moore et al. (2008) concluded that MTG proteins act downstream of beta-catenin in the Wnt signaling pathway.
Tu et al. (2016) identified a novel corepressor protein, CBFA2T2, that regulates pluripotency and germline specification in mice. Cbfa2t2-null mice displayed severe defects in primordial germ cell maturation and epigenetic reprogramming. CBFA2T2 forms a biochemical complex with PRDM14 (611781), a germline-specific transcription factor. Mechanistically, CBFA2T2 oligomerizes to form a scaffold upon which PRDM14 and OCT4 (POU5F1; 164177) are stabilized on chromatin. Thus, in contrast to the traditional 'passenger' role of a corepressor, CBFA2T2 functions synergistically with transcription factors at the crossroads of the fundamental developmental plasticity between uni- and pluripotency.
Morohoshi et al. (2000) determined that the CBFA2T2 gene contains 14 exons and spans about 68 kb.
By fluorescence in situ hybridization, Fracchiolla et al. (1998) mapped the EHT gene to 20q11. By PCR of DNA from somatic cell hybrids, they further refined the mapping to 20q11.2-q11.3. Calabi and Cilli (1998) reported that MTG8 and the related genes MTGR1 and MTGR2 (603870) are each located close to a member of the syntrophin gene family (see 600027). One alternative MTGR1 promoter/5-prime exon is contained within the alpha-1-syntrophin (601017) locus, suggesting that the 2 genes are in opposite orientations.
Calabi, F., Cilli, V. CBFA2T1, a gene rearranged in human leukemia, is a member of a multigene family. Genomics 52: 332-341, 1998. [PubMed: 9790752] [Full Text: https://doi.org/10.1006/geno.1998.5429]
Fracchiolla, N. S., Colombo, G., Finelli, P., Maiolo, A. T., Neri, A. EHT, a new member of the MTG8/ETO gene family, maps on 20q11 region and is deleted in acute myeloid leukemias. (Letter) Blood 92: 3481-3484, 1998. [PubMed: 9787195]
Kitabayashi, I., Ida, K., Morohoshi, F., Yokoyama, A., Mitsuhashi, N., Shimizu, K., Nomura, N., Hayashi, Y., Ohki, M. The AML1-MTG8 leukemic fusion protein forms a complex with a novel member of the MTG8(ETO/CDR) family, MTGR1. Molec. Cell. Biol. 18: 846-858, 1998. [PubMed: 9447981] [Full Text: https://doi.org/10.1128/MCB.18.2.846]
Kumar, R., Cheney, K. M., McKirdy, R., Neilsen, P. M., Schulz, R. B., Lee, J., Cohen, J., Booker, G. W., Callen, D. F. CBFA2T3-ZNF652 corepressor complex regulates transcription of the E-box gene HEB. J. Biol. Chem. 283: 19026-19038, 2008. [PubMed: 18456661] [Full Text: https://doi.org/10.1074/jbc.M709136200]
Moore, A. C., Amann, J. M., Williams, C. S., Tahinci, E., Farmer, T. E., Martinez, J. A., Yang, G., Luce, K. S., Lee, E., Hiebert, S. W. Myeloid translocation gene family members associate with T-cell factors (TCFs) and influence TCF-dependent transcription. Molec. Cell. Biol. 28: 977-987, 2008. [PubMed: 18039847] [Full Text: https://doi.org/10.1128/MCB.01242-07]
Morohoshi, F., Mitani, S., Mitsuhashi, N., Kitabayashi, I., Takahashi, E., Suzuki, M., Munakata, N., Ohki, M. Structure and expression pattern of a human MTG8/ETO family gene, MTGR1. Gene 241: 287-295, 2000. [PubMed: 10675041] [Full Text: https://doi.org/10.1016/s0378-1119(99)00481-3]
Tu, S., Narendra, V., Yamaji, M., Vidal, S. E., Rojas, L. A., Wang, X., Kim, S. Y., Garcia, B. A., Tuschl, T., Stadtfeld, M., Reinberg, D. Co-repressor CBFA2T2 regulates pluripotency and germline development. Nature 534: 387-390, 2016. [PubMed: 27281218] [Full Text: https://doi.org/10.1038/nature18004]