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Molecular and Cellular Biology, April 2005, p. 2924-2937, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.2924-2937.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

MRG15 Regulates Embryonic Development and Cell Proliferation

Kaoru Tominaga,1* Bhakti Kirtane,1,{dagger} James G. Jackson,1,{dagger} Yuji Ikeno,1,2,{dagger} Takayoshi Ikeda,3 Christina Hawks,4 James R. Smith,5 Martin M. Matzuk,6,7,8 and Olivia M. Pereira-Smith1

Departments of Cellular and Structural Biology,1 Physiology,4 Pathology, Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, STCBM,5 Research Service, Audie Murphy VA Hospital (STVHCS), San Antonio,2 Departments of Pathology,6 Molecular and Cellular Biology,7 Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas,8 The Radiation Effects Research Foundation, Nagasaki, Japan3

Received 19 October 2004/ Returned for modification 20 November 2004/ Accepted 13 January 2005

MRG15 is a highly conserved protein, and orthologs exist in organisms from yeast to humans. MRG15 associates with at least two nucleoprotein complexes that include histone acetyltransferases and/or histone deacetylases, suggesting it is involved in chromatin remodeling. To study the role of MRG15 in vivo, we generated knockout mice and determined that the phenotype is embryonic lethal, with embryos and the few stillborn pups exhibiting developmental delay. Immunohistochemical analysis indicates that apoptosis in Mrg15–/– embryos is not increased compared with wild-type littermates. However, the number of proliferating cells is significantly reduced in various tissues of the smaller null embryos compared with control littermates. Cell proliferation defects are also observed in Mrg15–/– mouse embryonic fibroblasts. The hearts of the Mrg15–/– embryos exhibit some features of hypertrophic cardiomyopathy. The increase in size of the cardiomyocytes is most likely a response to decreased growth of the cells. Mrg15–/– embryos appeared pale, and microarray analysis revealed that {alpha}-globin gene expression was decreased in null versus wild-type embryos. We determined by chromatin immunoprecipitation that MRG15 was recruited to the {alpha}-globin promoter during dimethyl sulfoxide-induced mouse erythroleukemia cell differentiation. These findings demonstrate that MRG15 has an essential role in embryonic development via chromatin remodeling and transcriptional regulation.

* Corresponding author. Mailing address: Department of Cellular and Structural Biology, Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, STCBM Bldg. 3.100, 15355 Lambda Dr., San Antonio, TX 78245-3207. Phone: (210) 562-5061. Fax: (210) 562-5093. E-mail: tominaga{at}uthscsa.edu.

{dagger} B.K., J.G.J., and Y.I. contributed equally to this work.

Molecular and Cellular Biology, April 2005, p. 2924-2937, Vol. 25, No. 8
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.8.2924-2937.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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