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PMID: 18722178 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Genome-wide analysis of the H3K4 histone demethylase RBP2 reveals a transcriptional program controlling differentiation.

Molecular cell ·Vol. 31 ·No. 4 ·2008-08-22 ·Pages 520-530

Lopez-Bigas N, Kisiel TA, DeWaal DC, Holmes KB, Volkert TL, Gupta S, Love J, Murray HL, Young RA, Benevolenskaya EV

Abstract

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.

MeSH Terms

Binding Sites Cell Differentiation/genetics Gene Expression Profiling Gene Expression Regulation Genome, Human/genetics Genomics Histones/metabolism Humans Intracellular Signaling Peptides and Proteins/metabolism Lysine/metabolism Methylation Mitochondria/enzymology Models, Biological Nucleosomes/enzymology Oxidoreductases, N-Demethylating/metabolism Promoter Regions, Genetic/genetics Protein Binding Repressor Proteins/metabolism Retinoblastoma-Binding Protein 2 Sequence Analysis, DNA Transcription Factors/metabolism Transcription, Genetic Tumor Suppressor Proteins/metabolism

Chemicals

Histones Intracellular Signaling Peptides and Proteins Nucleosomes Repressor Proteins Transcription Factors Tumor Suppressor Proteins KDM5A protein, human Retinoblastoma-Binding Protein 2 Oxidoreductases, N-Demethylating Lysine

Authors & Affiliations

10 authors, click to expand affiliations / ORCID

Lopez-Bigas Nuria

Research Unit on Biomedical Informatics, Experimental and Health Science Department, Universitat Pompeu Fabra, Barcelona 08080, Spain.

Kisiel Tomasz A

Research Unit on Biomedical Informatics, Experimental and Health Science Department, Universitat Pompeu Fabra, Barcelona 08080, Spain.

DeWaal Dannielle C

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA.

Holmes Katie B

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA.

Volkert Tom L