Alternative titles; symbols
HGNC Approved Gene Symbol: MAFG
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:81,918,270-81,931,244 (from NCBI)
Globin gene expression is regulated through nuclear factor erythroid-2 (NFE2) elements located in enhancer-like locus control regions positioned many kb upstream of alpha- and beta-gene clusters. NFE2 DNA-binding activity consists of a heterodimer containing a ubiquitous small Maf protein (MafF, 604877; MafG; or MafK, 600197) and the tissue-restricted protein p45 NFE2 (601490). Both subunits are members of the activator protein-1-like superfamily of basic leucine zipper (bZIP) proteins (see 165160) (summary by Blank et al., 1997).
Blank et al. (1997) isolated a cDNA encoding human MAFG, which is expressed in a wide array of tissues and cell lines. They showed that human MAFG protein, like its chicken counterpart, is able to dimerize with p45 NFE2. A p45/MAFG heterodimer was fully functional in supporting expression of alpha- and beta-globin genes and in promoting erythroid differentiation in a p45-deficient mouse erythroleukemia cell line.
Toki et al. (1997) cloned a cDNA encoding the 162-amino acid MAFG polypeptide. Northern blot analysis revealed that it was widely expressed, with highest expression occurring in skeletal muscle. Toki et al. (1997) found that MAFG forms heterodimers not only with p45, but also with NFE2-related factor 1 (NRF1; 163260) and NFE2-related factor 2 (600492); these heterodimers bound to NFE2 sites in vitro. In vivo, MAFG/p45 and MAFG/NRF1 heterodimers stimulated transcription from NFE2 sites. Similar results were found with MAFK.
Blank et al. (1997) showed that human MAFG contains at least 3 exons, which are separated by small introns. The first exon is not translated.
Katsuoka et al. (2003) showed that MafG and MafK are expressed in CNS neurons and that mafG/mafK compound mutant mice display a hypertonic motor disorder with myoclonus and abnormal responses to startle stimuli. The neuronal degeneration was coincident with MARE-dependent transcriptional abnormalities, such as Bach protein (see 602751) mislocalization. The authors hypothesized that glycine receptor abnormalities may be involved.
Wheeler et al. (2020) identified astrocytes in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis that were characterized by decreased expression of NRF2 (600492) and increased expression of MAFG, which cooperates with MAT2-alpha (MAT2A; 601468) to promote DNA methylation and represses antioxidant and antiinflammatory transcriptional programs. Granulocyte-macrophage colony-stimulating factor (GMCSF; 138960) signaling in astrocytes drives the expression of MAFG and MAT2-alpha and proinflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis.
Blank et al. (1997) mapped the MAFG gene to 17q25 by fluorescence in situ hybridization. Iwata et al. (1998) used FISH to confirm the MAFG map location at 17q25.
Motohashi et al. (2000) found that mouse embryos expressing abundant transgene-derived Mafk died of severe anemia, while lines expressing lower levels of small Maf lived to adulthood. Megakaryocytes from the latter overexpressing lines exhibited reduced proplatelet formation and MARE (Maf recognition element)-dependent transcription, phenocopying Mafg-null mice (see Shavit et al. (1998)). When the Mafg-null mice were bred to small Maf-overexpressing transgenic animals, both loss- and gain-of-function phenotypes were reversed.
Blank, V., Kim, M. J., Andrews, N. C. Human MAFG is a functional partner for p45 NF-E2 in activating globin gene expression. Blood 89: 3925-3935, 1997. [PubMed: 9166829]
Blank, V., Knoll, J. H. M., Andrews, N. C. Molecular characterization and localization of the human MafG gene. Genomics 44: 147-149, 1997. [PubMed: 9286713] [Full Text: https://doi.org/10.1006/geno.1997.4847]
Iwata, T., Kogame, K., Toki, T., Yokoyama, M., Yamamoto, M., Ito, E. Structure and chromosome mapping of the human small maf genes MAFG and MAFK. Cytogenet. Cell Genet. 82: 88-90, 1998. [PubMed: 9763667] [Full Text: https://doi.org/10.1159/000015071]
Katsuoka, F., Motohashi, H., Tamagawa, Y., Kure, S., Igarashi, K., Engel, J. D., Yamamoto, M. Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response. Molec. Cell. Biol. 23: 1163-1174, 2003. [PubMed: 12556477] [Full Text: https://doi.org/10.1128/MCB.23.4.1163-1174.2003]
Motohashi, H., Katsuoka, F., Shavit, J. A., Engel, J. D., Yamamoto, M. Positive or negative MARE-dependent transcriptional regulation is determined by the abundance of small Maf proteins. Cell 103: 865-875, 2000. [PubMed: 11136972] [Full Text: https://doi.org/10.1016/s0092-8674(00)00190-2]
Shavit, J. A., Motohashi, H., Onodera, K., Akasaka, J., Yamamoto, M., Engel, J. D. Impaired megakaryopoiesis and behavioral defects in mafG-null mutant mice. Genes Dev. 12: 2164-2174, 1998. [PubMed: 9679061] [Full Text: https://doi.org/10.1101/gad.12.14.2164]
Toki, T., Itoh, J., Kitazawa, J., Arai, K., Hatakeyama, K., Akasaka, J., Igarashi, K., Nomura, N., Yokoyama, M., Yamamoto, M., Ito, E. Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif. Oncogene 14: 1901-1910, 1997. [PubMed: 9150357] [Full Text: https://doi.org/10.1038/sj.onc.1201024]
Wheeler, M. A., Clark, I. C., Tjon, E. C., Li, Z., Zandee, S. E. J., Couturier, C. P., Watson, B. R., Scalisi, G., Alkwai, S., Rothhammer, V., Rotem, A., Heyman, J. A., and 10 others. MAFG-driven astrocytes promote CNS inflammation. Nature 578: 593-599, 2020. [PubMed: 32051591] [Full Text: https://doi.org/10.1038/s41586-020-1999-0]