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Developmental Genetics
Developmental Genetics
Research
The Develpmental Genetics Research Group fulfills a double role within RCAI.A large portion of the manpower and financial resources of the group is devoted to the maintenance of a high-standard mouse facility at RCAI. Through the Animal Core Facility, the group is also responsible for the generation of knock-out and transgenic animals for the various research laboratories at the center. At the same time, the laboratory is pursuing a research program to elucidate the molecular mechanisms underlying the epigenetic regulation mediated by Polycomb group (PcG) genes in development.PcG genes have been first isolated in Drosophila Melanogaster as a group of genes required in maintenance of segmental identity and shown to be structurally and functionally conserved in mammals.Genetic analyses for mammalian PcG proteins revealed their roles not only in the anterior-posterior specifications but also in cellular proliferation, differentiation, and senescence. Particularly, significant impacts of PcG functions upon lymphocyte and lymphoid organ development have repeatedly been reported. PcG gene products form at least two different multimeric protein complexes, one mediates histone H3-K27 trimethylation and another H2A-K119 ubiquitinylation, on the chromatin. It is, however, unknown how PcG complexes mediate transcriptional repression and, consequently, exert their biological functions. To elucidate the molecular nature for PcG-mediated transcriptional regulation, we have been focusing following issues; (1) association of PcG proteins to their targets, (2) molecular mechanisms underlying PcG-mediated repression, and (3) Real-time imaging of PcG repressive complexes.
The Develpmental Genetics Research Group fulfills a double role within RCAI.A large portion of the manpower and financial resources of the group is devoted to the maintenance of a high-standard mouse facility at RCAI. Through the Animal Core Facility, the group is also responsible for the generation of knock-out and transgenic animals for the various research laboratories at the center. At the same time, the laboratory is pursuing a research program to elucidate the molecular mechanisms underlying the epigenetic regulation mediated by Polycomb group (PcG) genes in development.PcG genes have been first isolated in Drosophila Melanogaster as a group of genes required in maintenance of segmental identity and shown to be structurally and functionally conserved in mammals.Genetic analyses for mammalian PcG proteins revealed their roles not only in the anterior-posterior specifications but also in cellular proliferation, differentiation, and senescence. Particularly, significant impacts of PcG functions upon lymphocyte and lymphoid organ development have repeatedly been reported. PcG gene products form at least two different multimeric protein complexes, one mediates histone H3-K27 trimethylation and another H2A-K119 ubiquitinylation, on the chromatin. It is, however, unknown how PcG complexes mediate transcriptional repression and, consequently, exert their biological functions. To elucidate the molecular nature for PcG-mediated transcriptional regulation, we have been focusing following issues; (1) association of PcG proteins to their targets, (2) molecular mechanisms underlying PcG-mediated repression, and (3) Real-time imaging of PcG repressive complexes.
Nuclear localizations of Rnf2/Ring1B (green) and Mel18 (red)
in mouse embryonic fibroblast (MEF) (left) and
trophoblast stem (TS) cell (right).
In MEFs, Rnf2 and Mel18, respectively, show a lot of speckled structures separately or together and also filamentous structures through nucleus. In contrast, in TS cells both proteins are significantly located on the inactive X chromosome.
in mouse embryonic fibroblast (MEF) (left) and
trophoblast stem (TS) cell (right).
In MEFs, Rnf2 and Mel18, respectively, show a lot of speckled structures separately or together and also filamentous structures through nucleus. In contrast, in TS cells both proteins are significantly located on the inactive X chromosome.
The role of mammalian Polycomb Scmh1 at the XY body in pachytene spermatocytes
The product of the Scmh1 gene, a mammalian homolog of Drosophila Sex comb on midleg, is a constituent of the mammalian Polycomb repressive complexes 1 (PRC1). XY body is a specialized and visibly distinct domain within the nucleus of a mammalian pachytene spermatocytes. Early in the formation of the XY body, phosphorylated histone H2A.X (γH2A.X) and ubiquitylated H2A (uH2A) are enriched at the XY body and then X and Y chromosomes undergo sequential changes in their histone modifications, which correlate with transcriptional status of sex chromosomes. During progression through the pachytene stage, Scmh1 was shown to be excluded from the XY body together with other PRC1 components such as Phc1, Phc2, Rnf110, Bmi1 and Cbx2. Apoptotic elimination of Scmh1-/- spermatocytes is accompanied by preceding failure of several specific chromatin modification at the XY body whereas synapsis of homologous autosomes is not affected. Restoration of defects in Scmh1-/- spermatocytes by Phc2 mutation indicates that Scmh1 exerts its molecular functions via its interaction with PRC1. Therefore, for the first time we have been able to indicate a functional involvement of PRC1 during the meiotic prophase of male germ cells and a regulatory role of Scmh1 for PRC1, which involves sex chromosomes.
The product of the Scmh1 gene, a mammalian homolog of Drosophila Sex comb on midleg, is a constituent of the mammalian Polycomb repressive complexes 1 (PRC1). XY body is a specialized and visibly distinct domain within the nucleus of a mammalian pachytene spermatocytes. Early in the formation of the XY body, phosphorylated histone H2A.X (γH2A.X) and ubiquitylated H2A (uH2A) are enriched at the XY body and then X and Y chromosomes undergo sequential changes in their histone modifications, which correlate with transcriptional status of sex chromosomes. During progression through the pachytene stage, Scmh1 was shown to be excluded from the XY body together with other PRC1 components such as Phc1, Phc2, Rnf110, Bmi1 and Cbx2. Apoptotic elimination of Scmh1-/- spermatocytes is accompanied by preceding failure of several specific chromatin modification at the XY body whereas synapsis of homologous autosomes is not affected. Restoration of defects in Scmh1-/- spermatocytes by Phc2 mutation indicates that Scmh1 exerts its molecular functions via its interaction with PRC1. Therefore, for the first time we have been able to indicate a functional involvement of PRC1 during the meiotic prophase of male germ cells and a regulatory role of Scmh1 for PRC1, which involves sex chromosomes.