Biomedical subjects

Mitsuhiro Endoh

Publications and source records attributed to Mitsuhiro Endoh.

4 recordsLinked to original sources

PubMed2006

Stem cells primed for action: polycomb repressive complexes restrain the expression of lineage-specific regulators in embryonic stem cells.

Stem cells are characterised by a capacity to self renew and generate progeny capable of differentiating along several defined lineage paths. Embryonic Stem (ES) cells are derived from the inner cell mass (ICM) of early-stage embryos and can contribute to all tissues of the developing embryo. Discovering how ES cell pluripotency and lineage induction is achieved is important for understanding normal development and for successfully applying stem cell-based therapies. A series of recent studies have shown that the chromatin profile of ES cells is unusual and have revealed a critical role for the Polycomb Repressive Complexes (PRCs) in maintaining pluripotency. In human and mouse ES cells many genes that encode transcription factors that are required for lineage specification bind PRC2 and carry bivalent (or opposing) histone signatures, being enriched for conventional indicators of active chromatin such as acetylated H3K9 and methylated H3K4, while lying within domains of repressive trimethylated H3K27. Mutant ES cells that lack H3K27 methylation inappropriately expressed these genes showing that PRC2 represses lineage-specific gene programs in ES cells. Here we discuss the implications of these new discoveries and explore the interdependence of PRC1 and PRC2 in regulating lineage-specific gene expression in ES cells.

Animals↗

PubMed2006

Mammalian Polycomb complexes are required for Peyer's patch development by regulating lymphoid cell proliferation.

The vertebrate Polycomb Group (PcG) genes encode proteins that form large multimeric and chromatin-associated complexes implicated in the stable repression of developmentally essential genes. Rnf110 and Phc2 are shown to be components of mammalian PcG multimeric complexes in HeLa cells. Here we report defects in Peyer's patch (PP) development in Rnf110 mutant mice, which is synergically exaggerated by Phc2 mutation. PP development involves a series of inductive interactions and subsequent differentiation and proliferation between lymphoid and mesenchymal cells in late gestational stage. Rnf110 and Phc2 mutations impair development of PP anlagen by affecting proliferation of lymphoid lineage cells populated in PP anlagen in gene-dosage dependent manner. We suggest that PcG complexes may act to mediate certain inductive signals maybe through IL-7Ralpha to allow sufficient proliferation of lymphoid inducer cells during PP organogenesis.

Animals↗

PubMed2006

Distinct roles of Polycomb group gene products in transcriptionally repressed and active domains of Hoxb8.

To address the molecular mechanisms underlying Polycomb group (PcG)-mediated repression of Hox gene expression, we have focused on the binding patterns of PcG gene products to the flanking regions of the Hoxb8 gene in expressing and non-expressing tissues. In parallel, we followed the distribution of histone marks of transcriptionally active H3 acetylated on lysine 9 (H3-K9) and methylated on lysine 4 (H3-K4), and of transcriptionally inactive chromatin trimethylated on lysine 27 (H3-K27). Chromatin immunoprecipitation revealed that the association of PcG proteins, and H3-K9 acetylation and H3-K27 trimethylation around Hoxb8 were distinct in tissues expressing and not expressing the gene. We show that developmental changes of these epigenetic marks temporally coincide with the misexpression of Hox genes in PcG mutants. Functional analyses, using mutant alleles impairing the PcG class 2 component Rnf2 or the Suz12 mutation decreasing H3-K27 trimethylation, revealed that interactions between class 1 and class 2 PcG complexes, mediated by trimethylated H3-K27, play decisive roles in the maintenance of Hox gene repression outside their expression domain. Within the expression domains, class 2 PcG complexes appeared to maintain the transcriptionally active status via profound regulation of H3-K9 acetylation. The present study indicates distinct roles for class 2 PcG complexes in transcriptionally repressed and active domains of Hoxb8 gene.

Animals↗

PubMed2002

SCL/tal-1-dependent process determines a competence to select the definitive hematopoietic lineage prior to endothelial differentiation.

Hematopoiesis in most vertebrate species occurs in two distinct phases, primitive and definitive, which diverge from FLK1(+)VE-cadherin(-) mesoderm and FLK1(+)VE-cadherin(+) endothelial cells (EC), respectively. This study aimed at determining the stage at which hematopoietic lineage fate is determined by manipulating the SCL/tal-1 expression that is known to be essential for the early development of the primitive and definitive hematopoietic systems. We established SCL-null ES cell lines in which SCL expression is rescued by tamoxifen-inducible Cre recombinase-loxP site-mediated recombination. While no hematopoietic cells (HPC) were detected in SCL-null ES cell differentiation cultures, SCL gene reactivation from day 2 to day 4 after initiation of differentiation could rescue both primitive and definitive hematopoiesis. SCL reactivation at later phases was ineffective. Moreover, generation of VE-cadherin(+) EC that can give rise to definitive HPC required SCL reactivation prior to VE-cadherin expression. These results indicated that the competence to become HPC is acquired at the mesodermal stage by a SCL-dependent process that takes place independently of determination of endothelial fate.

Animals↗