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The mSin3A chromatin-modifying complex is essential for embryogenesis and T-cell development.

Cowley, Shaun M and Iritani, Brian M and Mendrysa, Susan M and Xu, Tina and Cheng, Pei Feng and Yada, Jason and Liggitt, H Denny and Eisenman, Robert N (2005) The mSin3A chromatin-modifying complex is essential for embryogenesis and T-cell development. Molecular and cellular biology, 25 (16). pp. 6990-7004. ISSN 0270-7306

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Article URL: http://mcb.asm.org/cgi/content/full/25/16/6990

Abstract

The corepressor mSin3A is the core component of a chromatin-modifying complex that is recruited by multiple gene-specific transcriptional repressors. In order to understand the role of mSin3A during development, we generated constitutive germ line as well as conditional msin3A deletions. msin3A deletion in the developing mouse embryo results in lethality at the postimplantation stage, demonstrating that it is an essential gene. Blastocysts derived from preimplantation msin3A null embryos and mouse embryo fibroblasts (MEFs) lacking msin3A display a significant reduction in cell division. msin3A null MEFs also show mislocalization of the heterochromatin protein, HP1alpha, without alterations in global histone acetylation. Heterozygous msin3A(+/-) mice with a systemic twofold decrease in mSin3A protein develop splenomegaly as well as kidney disease indicative of a disruption of lymphocyte homeostasis. Conditional deletion of msin3A from developing T cells results in reduced thymic cellularity and a fivefold decrease in the number of cytotoxic (CD8) T cells, while helper (CD4) T cells are unaffected. We show that CD8 development is dependent on mSin3A at a step downstream of T-cell receptor signaling and that loss of mSin3A specifically decreases survival of double-positive and CD8 T cells. Thus, msin3A is a pleiotropic gene which, in addition to its role in cell cycle progression, is required for the development and homeostasis of cells in the lymphoid lineage.

Item Type: Article
Additional Information: This article is freely available in PubMed Central and at the journal's website via the Article URL above.
DOI: 10.1128/MCB.25.16.6990-7004.2005
PubMed ID: 16055712
PMCID: PMC1190252
Grant Numbers: RO1CA57138, R01AI0535468, 5RO1HD18184, 5RO1JL65898
Keywords or MeSH Headings: Animals; Apoptosis; Blastocyst; Blotting, Western; CD4-Positive T-Lymphocytes/metabolism; CD8-Positive T-Lymphocytes/metabolism; Cell Cycle; Cell Differentiation; Cell Lineage; Cell Proliferation; Cells, Cultured; Chromatin/chemistry/metabolism; Chromosomal Proteins, Non-Histone/metabolism; Exons; Fibroblasts/cytology/metabolism; Flow Cytometry; Gene Deletion; Gene Expression Regulation, Developmental; Genotype; Glomerulonephritis, Membranous; Heterochromatin/metabolism; Heterozygote; Mice; Mice, Transgenic; Models, Biological; Models, Genetic; Recombination, Genetic; Repressor Proteins/physiology; Splenomegaly; T-Lymphocytes/cytology/metabolism; T-Lymphocytes, Cytotoxic/cytology; Thymus Gland/cytology; Time Factors;
Subjects: Molecules > Proteins > Transcription factors
Cell Types > Blood and Immune Cells > T-Lymphocytes
Molecules > Chromosomes > Chromatin
Cellular and Organismal Processes > Development
Depositing User: Library Staff
Date Deposited: 16 Dec 2008 23:26
Last Modified: 13 May 2010 22:41
URI: http://authors.fhcrc.org/id/eprint/207

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