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).

Location of the M33 gene on chromosome 11.

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, histologically female internally, normal ovaries and external genitalia.[16]

References

  1. 1 2 3 Wang G, Horsley D, Ma A, Otte AP, Hutchings A, Butcher GW, Singh PB (1997). "M33, a mammalian homologue of Drosophila Polycomb localises to euchromatin within interphase nuclei but is enriched within the centromeric heterochromatin of metaphase chromosomes". Cytogenetics and Cell Genetics. 78 (1): 50–5. doi:10.1159/000134626. PMID 9345907.
  2. 1 2 Pearce JJ, Singh PB, Gaunt SJ (April 1992). "The mouse has a Polycomb-like chromobox gene". Development. 114 (4): 921–9. PMID 1352241.
  3. ↑ 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.
  4. ↑ Orlando V, Paro R (December 1993). "Mapping Polycomb-repressed domains in the bithorax complex using in vivo formaldehyde cross-linked chromatin". Cell. 75 (6): 1187–98. doi:10.1016/0092-8674(93)90328-n. PMID 7903220.
  5. ↑ Katoh-Fukui Y, Tsuchiya R, Shiroishi T, Nakahara Y, Hashimoto N, Noguchi K, Higashinakagawa T (June 1998). "Male-to-female sex reversal in M33 mutant mice". Nature. 393 (6686): 688–92. doi:10.1038/31482. PMID 9641679.
  6. ↑ "M33 (34): sc-136387" (PDF). Santa Cruz Biotechnology, Inc.
  7. ↑ Katoh-Fukui Y, Owaki A, Toyama Y, Kusaka M, Shinohara Y, Maekawa M, Toshimori K, Morohashi K (September 2005). "Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression". Blood. 106 (5): 1612–20. doi:10.1182/blood-2004-08-3367. PMID 15899914.
  8. ↑ Hirose S, Komoike Y, Higashinakagawa T (September 2006). "Identification of a nuclear localization signal in mouse polycomb protein, M33". Zoological Science. 23 (9): 785–91. doi:10.2108/zsj.23.785. PMID 17043400.
  9. ↑ Hashimoto N, Brock HW, Nomura M, Kyba M, Hodgson J, Fujita Y, Takihara Y, Shimada K, Higashinakagawa T (April 1998). "RAE28, BMI1, and M33 are members of heterogeneous multimeric mammalian Polycomb group complexes". Biochemical and Biophysical Research Communications. 245 (2): 356–65. doi:10.1006/bbrc.1998.8438. PMID 9571155.
  10. ↑ Bel-Vialar S, Coré N, Terranova R, Goudot V, Boned A, Djabali M (August 2000). "Altered retinoic acid sensitivity and temporal expression of Hox genes in polycomb-M33-deficient mice". Developmental Biology. 224 (2): 238–49. doi:10.1006/dbio.2000.9791. PMID 10926763.
  11. ↑ Baumann C, De La Fuente R (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. PMC 3244348. PMID 22200029.
  12. ↑ Ono M, Harley VR (February 2013). "Disorders of sex development: new genes, new concepts". Nature Reviews. Endocrinology. 9 (2): 79–91. doi:10.1038/nrendo.2012.235. PMID 23296159.
  13. ↑ Coré N, Bel S, Gaunt SJ, Aurrand-Lions M, Pearce J, Fisher A, Djabali M (February 1997). "Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice". Development. 124 (3): 721–9. PMID 9043087.
  14. 1 2 Vidal M (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): 355–70. doi:10.1387/ijdb.082690mv. PMID 19412891.
  15. ↑ Schoorlemmer J, Marcos-Gutiérrez C, Were F, Martínez R, García E, Satijn DP, Otte AP, Vidal M (October 1997). "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): 5930–42. doi:10.1093/emboj/16.19.5930. PMC 1170224. PMID 9312051.
  16. ↑ Biason-Lauber A, Konrad D, Meyer M, DeBeaufort C, Schoenle EJ (May 2009). "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene". American Journal of Human Genetics. 84 (5): 658–63. doi:10.1016/j.ajhg.2009.03.016. PMC 2680992. PMID 19361780.
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