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, Oct 03, 2015
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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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    ABSTRACT: All mature blood cells derive from hematopoietic stem cells through gradual restriction of their cell fate potential and acquisition of specialized functions. Lineage specification and cell commitment require the establishment of specific transcriptional programs involving the activation of lineage-specific genes and the repression of lineage-inappropriate genes. This process requires the concerted action of transcription factors (TFs) and epigenetic modifying enzymes. Within the hematopoietic system, B lymphopoiesis is one of the most-studied differentiation programs. Loss of function studies allowed the identification of many TFs and epigenetic modifiers required for B cell development. The usage of systematic analytical techniques such as transcriptome determination, genome-wide mapping of TF binding and epigenetic modifications, and mass spectrometry analyses, allowed to gain a systemic description of the intricate networks that guide B cell development. However, the precise mechanisms governing the interaction between TFs and chromatin are still unclear. Generally, chromatin structure can be remodeled by some TFs but in turn can also regulate (i.e., prevent or promote) the binding of other TFs. This conundrum leads to the crucial questions of who is on first, when, and how. We review here the current knowledge about TF networks and epigenetic regulation during hematopoiesis, with an emphasis on B cell development, and discuss in particular the current models about the interplay between chromatin and TFs.
    Frontiers in Immunology 04/2014; 5:156. DOI:10.3389/fimmu.2014.00156
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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.
    The EMBO Journal 03/2013; 32(8). DOI:10.1038/emboj.2013.66 · 10.43 Impact Factor
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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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    ABSTRACT: Following antigen recognition, naive T helper (Th; CD4+) cells can differentiate toward one of several effector lineages such as Th1 and Th2; each expressing distinctive transcriptional profiles of cytokine genes. These cytokines eventually instruct the strategy of the immune response. In our search for factors that propagate the transcriptional programs of differentiated Th cells, we previously found that Polycomb group (PcG) proteins, which are known as epigenetic regulators that maintain repressive chromatin states, bind differentially the signature cytokine genes. Unexpectedly, their binding to the Ifng (Interferon-g) in Th1 cells and Il4 (Interleukin-4) in Th2 cells, was correlated with transcriptional activation. Therefore, in this study we aimed to determine the functional role of PcG proteins in the regulation of the expression of the signature cytokine genes. PcG proteins were knocked down in primary and established murine Th cells using transduction of lentiviruses encoding short hairpin RNAs (shRNAs) directed to Mel-18, Ezh2, Eed and Ring1A, representative of two different PcG complexes. The chromatin structure and the binding activity of PcG proteins and transcription factors at the Ifng promoter were assessed by chromatin immunoprecipitation (ChIP) assays. Downregulation of PcG proteins was consistent with their function as positive regulators of the signature cytokine genes in primary and established Th1 and Th2 cells. Moreover, the PcG protein Mel-18 was necessary to recruit the Th1-lineage specifying transcription factor T-bet, and the T cell receptor (TCR)-inducible transcription factor NFAT1 to the Ifng promoter in Th1 cells. Nevertheless, our results suggest that PcG proteins can function also as conventional transcriptional repressors in Th cells of their known target the Hoxa7 gene. Our data support a model whereby the non-differentially expressed PcG proteins are recruited in a Th-lineage specific manner to their target genes to enforce the maintenance of specific transcriptional programs as transcriptional repressors or activators. Although our results suggest a direct effect of PcG proteins in the regulation of cytokine gene expression, indirect functions cannot be excluded.
    Journal of Molecular Signaling 05/2011; 6:5. DOI:10.1186/1750-2187-6-5
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