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Molecular and Cellular Biology, May 2006, p. 3565-3581, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3565-3581.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Essential Dosage-Dependent Functions of the Transcription Factor Yin Yang 1 in Late Embryonic Development and Cell Cycle Progression{dagger}

El Bachir Affar,1,¶ Frédérique Gay,1,¶ Yujiang Shi,1,{ddagger} Huifei Liu,1 Maite Huarte,1 Su Wu,1 Tucker Collins,2 En Li,3,§ and Yang Shi1*

Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,1 Department of Pathology, Boston Children's Hospital, Boston, Massachusetts 02115,2 Cardiovascular Research Center, Massachusetts General Hospital, and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 021293

Received 13 October 2005/ Returned for modification 28 November 2005/ Accepted 11 January 2006

Constitutive ablation of the Yin Yang 1 (YY1) transcription factor in mice results in peri-implantation lethality. In this study, we used homologous recombination to generate knockout mice carrying yy1 alleles expressing various amounts of YY1. Phenotypic analysis of yy1 mutant embryos expressing ~75%, ~50%, and ~25% of the normal complement of YY1 identified a dosage-dependent requirement for YY1 during late embryogenesis. Indeed, reduction of YY1 levels impairs embryonic growth and viability in a dose-dependent manner. Analysis of the corresponding mouse embryonic fibroblast cells also revealed a tight correlation between YY1 dosage and cell proliferation, with a complete ablation of YY1 inducing cytokinesis failure and cell cycle arrest. Consistently, RNA interference-mediated inhibition of YY1 in HeLa cells prevents cytokinesis, causes proliferative arrest, and increases cellular sensitivity to various apoptotic agents. Genome-wide expression profiling identified a plethora of YY1 target genes that have been implicated in cell growth, proliferation, cytokinesis, apoptosis, development, and differentiation, suggesting that YY1 coordinates multiple essential biological processes through a complex transcriptional network. These data not only shed new light on the molecular basis for YY1 developmental roles and cellular functions, but also provide insight into the general mechanisms controlling eukaryotic cell proliferation, apoptosis, and differentiation.

* Corresponding author. Mailing address: Harvard Medical School, Department of Pathology, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: (617) 432-4318. Fax: (617) 432-6687. E-mail: yang_shi{at}hms.harvard.edu.

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

Equal contribution.

{ddagger} Present address: Department of Biological Chemistry and Molecular Pharmacology, Brigham and Women's Hospital, Boston, MA 02115.

§ Present address: Novartis Institutes for Biomedical Research, Cambridge, MA 02139.

Molecular and Cellular Biology, May 2006, p. 3565-3581, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3565-3581.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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