Phenotypic transcription factors epigenetically mediate cell growth control

*Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655; and
^¶Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas, Universidad de Concepción, Casilla 160-C, Concepción, Chile

Edited by Sheldon Penman, Massachusetts Institute of Technology, Cambridge, MA, and approved March 12, 2008 (received for review January 30, 2008)

Abstract

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.

Footnotes

^‖To whom correspondence should be addressed. E-mail: janet.stein{at}umassmed.edu
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.
↵ ^†Present address: Dana–Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.
↵ ^‡Present address: Wolf, Greenfield & Sacks, P.C., 600 Atlantic Avenue, Boston, MA 02210-2206.
↵ ^§Permanent address: School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0800970105/DCSupplemental.