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/EBPbeta] 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/EBPbeta 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.
Ali
Syed A
SA
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Zaidi
Sayyed K
SK
Dacwag
Caroline S
CS
Salma
Nunciada
N
Young
Daniel W
DW
Shakoori
Abdul R
AR
Montecino
Martin A
MA
Lian
Jane B
JB
van Wijnen
Andre J
AJ
Imbalzano
Anthony N
AN
Stein
Gary S
GS
Stein
Janet L
JL
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D004275:DNA, Ribosomal / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D017570:MyoD Protein / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism; D009697:Nucleolus Organizer Region; D010641:Phenotype; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D021381:Protein Transport; D012335:RNA, Ribosomal / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D004275:DNA, Ribosomal; D017570:MyoD Protein; D018008:Myogenin; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; D014157:Transcription Factors; C063844:transcription factor UBF