The Role of mel-18, a Mammalian Polycomb Group Gene, during IL-7–Dependent Proliferation of Lymphocyte Precursors

Core Research for Evolution Science and Technology, Japan Science and Technology Corporation, and Division of Molecular Immunology, Center for Biomedical Science, School of Medicine, Chiba University.
Immunity (Impact Factor: 21.56). 08/1997; 7(1):135-46. DOI: 10.1016/S1074-7613(00)80516-6
Source: PubMed


mel-18 is a mammalian homolog of Drosophila melanogaster Polycomb group genes. Mice lacking the mel-18 gene show a posterior transformation of the axial skeleton, severe combined immunodeficiency, and a food-passing disturbance in the lower intestine due to hypertrophy of the smooth muscle layer. In this study, the severe combined immunodeficiency observed in mel-18 mutant mice is correlated with the impaired mitotic response of lymphocyte precursors upon interleukin-7 stimulation. Strikingly, the axial skeleton and lymphoid phenotypes are identical in both mel-18 and bmi-1 mutants, indicating that the Mel-18 and Bmi-1 gene products might act in the same genetic cascade. These results suggest that mammalian Polycomb group gene products are involved in cell cycle progression in the immune system.

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Available from: Masamoto Kanno
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    • "Many PcG deficiencies correlate with defective development and/or activation of lymphocytes. For example, inactivation of Bmi1 or mel-18 causes a severe block in B cell development that leads to B cell lymphopenia (68, 69). By contrast, deficiency in Cbx2 does not affect lymphocyte development but alters splenic B cell response to lipopolysaccharide (LPS) (70). "
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    • "We previously showed that YY1 is a PcG protein, and is the only known mammalian PcG protein with DNA binding site specificity (Atchison et al, 2003; Srinivasan and Atchison, 2004; Srinivasan et al, 2005). PcG proteins comprise a family of proteins involved in haematopoietic development, epigenetic chromosomal condensation, stable transcriptional repression, control of cell proliferation, long distance interactions between DNA sequences, and stem cell self-renewal (van der Lugt et al, 1994; Alkema et al, 1995; Schumacher et al, 1996; Akasaka et al, 1997; Core et al, 1997; Lessard et al, 1999; Lessard and Sauvageau, 2003; Park et al, 2003; Lanzuolo et al, 2007). We found that YY1 can repress transcription in a PcG-dependent fashion and can recruit other PcG proteins to specific DNA sequences (Atchison et al, 2003; Srinivasan and Atchison, 2004). "
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    ABSTRACT: Conditional knock-out (KO) of Polycomb Group (PcG) protein YY1 results in pro-B cell arrest and reduced immunoglobulin locus contraction needed for distal variable gene rearrangement. The mechanisms that control these crucial functions are unknown. We deleted the 25 amino-acid YY1 REPO domain necessary for YY1 PcG function, and used this mutant (YY1ΔREPO), to transduce bone marrow from YY1 conditional KO mice. While wild-type YY1 rescued B-cell development, YY1ΔREPO failed to rescue the B-cell lineage yielding reduced numbers of B lineage cells. Although the IgH rearrangement pattern was normal, there was a selective impact at the Igκ locus that showed a dramatic skewing of the expressed Igκ repertoire. We found that the REPO domain interacts with proteins from the condensin and cohesin complexes, and that YY1, EZH2 and condensin proteins co-localize at numerous sites across the Ig kappa locus. Knock-down of a condensin subunit protein or YY1 reduced rearrangement of Igκ Vκ genes suggesting a direct role for YY1-condensin complexes in Igκ locus structure and rearrangement.
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    • "Mel-18 deficient mice have severe proliferative defects in lymphoid cells resulting in hypoplasia of spleen and thymus [44,63,64], and have less than 5% of the thymocytes of wild-type mice [65]. The differentiation of Mel-18-deficient Th2 cells is impaired, but not of Th1 [54]. "
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