A common set of gene regulatory networks links metabolism and growth inhibition.
Using genome-wide analysis of transcription factor occupancy, we investigated the mechanisms underlying three mammalian growth arrest pathways that require the pRB tumor suppressor family. We found that p130 and E2F4 cooperatively repress a common set of genes under each growth arrest condition and showed that growth arrest is achieved through repression of a core set of genes involved not only in cell cycle control but also mitochondrial biogenesis and metabolism. Motif-finding algorithms predicted the existence of nuclear respiratory factor-1 (NRF1) binding sites in E2F target promoters, and genome-wide factor binding analysis confirmed our predictions. We showed that NRF1, a factor known to regulate expression of genes involved in mitochondrial function, is a coregulator of a large number of E2F target genes. Our studies provide insights into E2F regulatory circuitry, suggest how factor occupancy can predict the expression signature of a given target gene, and reveal pathways deregulated in human tumors.
Cam
Hugh
H
Department of Pathology, MSB 504, New York University School of Medicine and New York University Cancer Institute, 550 First Avenue, New York, NY 10016, USA.
Balciunaite
Egle
E
Blais
Alexandre
A
Spektor
Alexander
A
Scarpulla
Richard C
RC
Young
Richard
R
Kluger
Yuval
Y
Dynlacht
Brian David
BD
D020816:Amino Acid Motifs; D017209:Apoptosis; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050704:E2F4 Transcription Factor; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005809:Genes, Regulator / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; C495633:NRF1 protein, human; D009687:Nuclear Proteins; D051266:Nuclear Respiratory Factor 1; D011506:Proteins; C493837:RBL2 protein, human; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors