This Article Full Text Full Text (PDF) Supplemental material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cowley, S. M. Articles by Eisenman, R. N. Search for Related Content PubMed PubMed Citation Articles by Cowley, S. M. Articles by Eisenman, R. N.

The mSin3A Chromatin-Modifying Complex Is Essential for Embryogenesis and T-Cell Development

Shaun M. Cowley,^1, Brian M. Iritani,² Susan M. Mendrysa,¹ Tina Xu,¹ Pei Feng Cheng,¹ Jason Yada,¹ H. Denny Liggitt,² and Robert N. Eisenman^1*

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington,¹ Department of Comparative Medicine, University of Washington School of Medicine, Seattle, Washington²

Received 29 March 2005/ Returned for modification 5 May 2005/ Accepted 18 May 2005

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, HP1, 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.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.

This article has been cited by other articles:

• David, G., Grandinetti, K. B., Finnerty, P. M., Simpson, N., Chu, G. C., DePinho, R. A. (2008). Specific requirement of the chromatin modifier mSin3B in cell cycle exit and cellular differentiation. Proc. Natl. Acad. Sci. USA 105: 4168-4172 [Abstract] [Full Text]  
• Kaji, K., Nichols, J., Hendrich, B. (2007). Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells. Development 134: 1123-1132 [Abstract] [Full Text]  
• Shiio, Y., Rose, D. W., Aur, R., Donohoe, S., Aebersold, R., Eisenman, R. N. (2006). Identification and Characterization of SAP25, a Novel Component of the mSin3 Corepressor Complex. Mol. Cell. Biol. 26: 1386-1397 [Abstract] [Full Text]