Phenotypic transcription factors epigenetically mediate cell growth control

Ribosomal RNA (rRNA) genes are down-regulated during osteogenesis, myogenesis, and adipogenesis, necessitating a mechanistic understanding of interrelationships between growth control and phenotype commitment. Here, we show that cell fate-determining factors [MyoD, myogenin (Mgn), Runx2, C/EBPβ] occ...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 18; pp. 6632 - 6637
Main Authors:	Ali, Syed A, Zaidi, Sayyed K, Dacwag, Caroline S, Salma, Nunciada, Young, Daniel W, Shakoori, Abdul R, Montecino, Martin A, Lian, Jane B, van Wijnen, Andre J, Imbalzano, Anthony N, Stein, Gary S, Stein, Janet L
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 06-05-2008 National Acad Sciences
Subjects:	Adipocytes Animals Biological Sciences Cell Differentiation Cell division Cell growth Cell Line Cell Lineage Cell lines Cell Proliferation Cells Cellular differentiation DNA, Ribosomal - genetics Down-Regulation - genetics Epigenesis, Genetic Gene expression Genes Mesoderm - cytology Mice MyoD Protein - metabolism Myogenin - metabolism Nucleolus Organizer Region Phenotype Pol1 Transcription Initiation Complex Proteins - metabolism Protein Binding Protein Biosynthesis Protein synthesis Protein Transport Proteins Repetitive Sequences, Nucleic Acid Ribosomal DNA RNA RNA polymerase RNA, Ribosomal - genetics rRNA genes Transcription factors Transcription Factors - metabolism Transcription, Genetic
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Summary:	Ribosomal RNA (rRNA) genes are down-regulated during osteogenesis, myogenesis, and adipogenesis, necessitating a mechanistic understanding of interrelationships between growth control and phenotype commitment. Here, we show that cell fate-determining factors [MyoD, myogenin (Mgn), Runx2, C/EBPβ] occupy rDNA loci and suppress rRNA expression during lineage progression, concomitant with decreased rRNA expression and reciprocal loss of occupancy by c-Myc, a proliferation-specific activator of rRNA transcription. We find interaction of phenotypic factors with the polymerase I activator upstream binding factor UBF-1 at interphase nucleoli, and this interaction is epigenetically retained on mitotic chromosomes at nucleolar organizing regions. Ectopic expression and RNA interference establish that MyoD, Mgn, Runx2, and C/EBPβ each functionally suppress rRNA genes and global protein synthesis. We conclude that epigenetic control of ribosomal biogenesis by lineage-specific differentiation factors is a general developmental mechanism for coordinate control of cell growth and phenotype.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Wolf, Greenfield & Sacks, P.C., 600 Atlantic Avenue, Boston, MA 02210-2206. Present address: Dana–Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Author contributions: S.A.A., S.K.Z., J.B.L., A.J.v.W., A.N.I., G.S.S., and J.L.S. designed research; S.A.A. and N.S. performed research; S.A.A., C.S.D., N.S., and A.N.I. contributed new reagents/analytic tools; S.A.A., S.K.Z., C.S.D., D.W.Y., M.A.M., J.B.L., A.J.v.W., A.N.I., G.S.S., and J.L.S. analyzed data; and S.A.A., S.K.Z., C.S.D., D.W.Y., A.R.S., M.A.M., J.B.L., A.J.v.W., A.N.I., G.S.S., and J.L.S. wrote the paper. Permanent address: School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan. Edited by Sheldon Penman, Massachusetts Institute of Technology, Cambridge, MA, and approved March 12, 2008
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0800970105