Genome-wide analysis of the H3K4 histone demethylase RBP2 reveals a transcriptional program controlling differentiation.
Retinoblastoma protein (pRB) mediates cell-cycle withdrawal and differentiation by interacting with a variety of proteins. RB-Binding Protein 2 (RBP2) has been shown to be a key effector. We sought to determine transcriptional regulation by RBP2 genome-wide by using location analysis and gene expression profiling experiments. We describe that RBP2 shows high correlation with the presence of H3K4me3 and its target genes are separated into two functionally distinct classes: differentiation-independent and differentiation-dependent genes. The former class is enriched by genes that encode mitochondrial proteins, while the latter is represented by cell-cycle genes. We demonstrate the role of RBP2 in mitochondrial biogenesis, which involves regulation of H3K4me3-modified nucleosomes. Analysis of expression changes upon RBP2 depletion depicted genes with a signature of differentiation control, analogous to the changes seen upon reintroduction of pRB. We conclude that, during differentiation, RBP2 exerts inhibitory effects on multiple genes through direct interaction with their promoters.
Lopez-Bigas
Nuria
N
Research Unit on Biomedical Informatics, Experimental and Health Science Department, Universitat Pompeu Fabra, Barcelona 08080, Spain.
Kisiel
Tomasz A
TA
Research Unit on Biomedical Informatics, Experimental and Health Science Department, Universitat Pompeu Fabra, Barcelona 08080, Spain.
DeWaal
Dannielle C
DC
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA.
Holmes
Katie B
KB
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA.
Volkert
Tom L
TL
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Gupta
Sumeet
S
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Love
Jennifer
J
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Murray
Heather L
HL
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Young
Richard A
RA
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Benevolenskaya
Elizaveta V
EV
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA. Electronic address: evb@uic.edu.
D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D008928:Mitochondria / Q000201:enzymology; D008954:Models, Biological; D009707:Nucleosomes / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D056485:Retinoblastoma-Binding Protein 2; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009707:Nucleosomes; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2; D010089:Oxidoreductases, N-Demethylating; D008239:Lysine