M33 (gene)
M33 is a gene.[1] It is a mammalian homologue of Drosophila Polycomb.[1] It localises to euchromatin within interphase nuclei, but it is enriched within the centromeric heterochromatin of metaphase chromosomes.[1] In mice, the official symbol of M33 gene styled Cbx2 and the official name chromobox 2 are maintained by the MGI. Also known as pc; MOD2. In human ortholog CBX2, synonyms CDCA6, M33, SRXY5 from orthology source HGNC. M33 was isolated by means of the structural similarity of its chromodomain.[2] It contains a region of homology shared by Xenopus and Drosophila in the fifth exon. [3] Polycomb genes in Drosophila mediate changes in higher-order chromatin structure to maintain the repressed state of developmentally regulated genes .[4] M33 deficiency interferes with steps upstream of the Y-chromosome-specific SRY gene may cause sex reversal.[5] It may also involved in the campomelic syndrome and neoplastic disorders linked to allele loss in this region.[6] Disruption of the murine M33 gene, displayed posterior transformation of the sternal ribs and vertebral columns .[7]
Gene location
The mouse M33 gene is located on the Chromosome 11, from base pair 119,022,962 to base pair 119,031,270 (Build GRCm38/mm10)(Map). Human homolog of M33, Chromobox homolog 2 (CBX2 ) is located on Chromosome 17, from base pair 79,777,188 to base pair 79,787,650(Build GRCh38.p2 )(Map).
Protein structure
This protein contains Chromo (CHRromatin Organization MOdifier) domain and nuclear localization signal motif.[8] The full-length M33 sequence encodes a 519 amino acid (aa) protein.[2]
Function and mechanism
The mouse Polycomb group (PcG) protein M33 maintains repressed states of developmentally important genes, including homeotic genes and forms nuclear complexes with other PcG members. e.g.BMI1.[9] It also direct and/or indirect controls the vicinity of Hox genes regulatory regions, which are the accessibility of retinoic acid response elements .[10] The deletion of Cbx2/M33 in mice results in male-to-female sex reversal, homeotic transformations of the axial skeleton, and growth retardation.[11] The expression of Sry and Sox9 genes in gonads of XY Cbx2-knockout mice is reduced, suggesting that Cbx2 is required for the expression of Sry in gonadal development.[12] Moreover, the deficient of M33 also possessed abnormally few nucleated cells in the thymus and spleen, due to the aberrant T-cell expansion.[13] In transiently transfected cells, M33 acts as a transcriptional repressor . Biochemical assays indicate that two murine proteins, Ring1A[14] and Ring1B[14] interact directly with the repressor domain of M33 and that Ring1A can also behave as a transcriptional repressor.[15]
Mutation
Katoh-Fukui et al. (1998) indicates that homozygous M33-mutant mice represent the first case in which male-to-female gonadal sex reversal results from a defect in a known recessive gene. In humans, the mutations in this gene are also associated with gonadal dysgenesis. Compound heterozygous mutations in M33 were identified in a patient with 46,XY DSD with histologicall female internaly, normal ovaries and external genitalia.[16]
References
- 1 2 3 Wang, G.; Horsley, D.; Ma, A.; Otte, A. P.; Hutchings, A.; Butcher, G. W.; Singh, P. B. (1997). "M33, a mammalian homologue of Drosophila Polycomb localises to euchromatin within interphase nuclei but is enriched within the centromeric heterochromatin of metaphase chromosomes". Cytogenetic and Genome Research. 78: 50. doi:10.1159/000134626.
- 1 2 Pearce, J. J.; Singh, P. B.; Gaunt, S. J. (1992-04-01). "The mouse has a Polycomb-like chromobox gene". Development (Cambridge, England). 114 (4): 921–929. ISSN 0950-1991. PMID 1352241.
- ↑ Reijnen, Marlene J.; Hamer, Karien M.; den Blaauwen, Jan L.; Lambrechts, Caro; Schoneveld, Ilse; van Driel, Roel; Otte, Arie P. (1995-09-01). "Polycomb and bmi-1 homologs are expressed in overlapping patterns in Xenopus embryos and are able to interact with each other". Mechanisms of Development. 53 (1): 35–46. doi:10.1016/0925-4773(95)00422-X.
- ↑ Orlando, V.; Paro, R. (1993-12-17). "Mapping Polycomb-repressed domains in the bithorax complex using in vivo formaldehyde cross-linked chromatin". Cell. 75 (6): 1187–1198. ISSN 0092-8674. PMID 7903220.
- ↑ Katoh-Fukui, Y.; Tsuchiya, R.; Shiroishi, T.; Nakahara, Y.; Hashimoto, N.; Noguchi, K.; Higashinakagawa, T. (1998-06-18). "Male-to-female sex reversal in M33 mutant mice". Nature. 393 (6686): 688–692. doi:10.1038/31482. ISSN 0028-0836. PMID 9641679.
- ↑ "M33 (34): sc-136387" (PDF). Santa Cruz Biotechnology, Inc.
- ↑ Katoh-Fukui, Yuko; Owaki, Akiko; Toyama, Yoshiro; Kusaka, Masatomo; Shinohara, Yuko; Maekawa, Mamiko; Toshimori, Kiyotaka; Morohashi, Ken-Ichirou (2005-09-01). "Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression". Blood. 106 (5): 1612–1620. doi:10.1182/blood-2004-08-3367. ISSN 0006-4971. PMID 15899914.
- ↑ Hirose, Sayako; Komoike, Yuta; Higashinakagawa, Toru (2006-09-01). "Identification of a Nuclear Localization Signal in Mouse Polycomb Protein, M33". Zoological Science. 23 (9): 785–791. doi:10.2108/zsj.23.785. ISSN 0289-0003.
- ↑ Hashimoto, N.; Brock, H. W.; Nomura, M.; Kyba, M.; Hodgson, J.; Fujita, Y.; Takihara, Y.; Shimada, K.; Higashinakagawa, T. (1998-04-17). "RAE28, BMI1, and M33 are members of heterogeneous multimeric mammalian Polycomb group complexes". Biochemical and Biophysical Research Communications. 245 (2): 356–365. doi:10.1006/bbrc.1998.8438. ISSN 0006-291X. PMID 9571155.
- ↑ "Altered Retinoic Acid Sensitivity and TemporalExpression of Hox Genes in Polycomb-M33-Deficient Mice". Developmental Biology. 224. doi:10.1006/dbio.2000.9791.
- ↑ Baumann, Claudia; De La Fuente, Rabindranath (2011-01-11). "Role of Polycomb Group Protein Cbx2/M33 in Meiosis Onset and Maintenance of Chromosome Stability in the Mammalian Germline". Genes. 2 (1): 59–80. doi:10.3390/genes2010059. ISSN 2073-4425. PMC 3244348.
- ↑ Ono, Makoto; Harley, Vincent R. (2013-02-01). "Disorders of sex development: new genes, new concepts". Nature Reviews. Endocrinology. 9 (2): 79–91. doi:10.1038/nrendo.2012.235. ISSN 1759-5037. PMID 23296159.
- ↑ Coré, N; Bel, S; Gaunt, S J; Aurrand-Lions, M; Pearce, J; Fisher, A. and; Djabali, M (1997-03-01). "Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice". ResearchGate. 124 (3). ISSN 0950-1991.
- 1 2 Vidal, Miguel (2009-01-01). "Role of polycomb proteins Ring1A and Ring1B in the epigenetic regulation of gene expression". The International Journal of Developmental Biology. 53 (2-3): 355–370. doi:10.1387/ijdb.082690mv. ISSN 1696-3547. PMID 19412891.
- ↑ Schoorlemmer, J; Marcos-Gutiérrez, C; Were, F; Martínez, R; García, E; Satijn, D P; Otte, A P; Vidal, M (1997-10-01). "Ring1A is a transcriptional repressor that interacts with the Polycomb-M33 protein and is expressed at rhombomere boundaries in the mouse hindbrain.". The EMBO Journal. 16 (19): 5930–5942. doi:10.1093/emboj/16.19.5930. ISSN 0261-4189. PMC 1170224.
- ↑ Biason-Lauber, Anna; Konrad, Daniel; Meyer, Monika; DeBeaufort, Carine; Schoenle, Eugen J. (2009-05-01). "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene". American Journal of Human Genetics. 84 (5): 658–663. doi:10.1016/j.ajhg.2009.03.016. ISSN 1537-6605. PMID 19361780.