Functional analysis of the transcription repressor PLU-1/JARID1B.
The PLU-1/JARID1B nuclear protein, which is upregulated in breast cancers, belongs to the ARID family of DNA binding proteins and has strong transcriptional repression activity. To identify the target genes regulated by PLU-1/JARID1B, we overexpressed or silenced the human PLU-1/JARID1B gene in human mammary epithelial cells by using adenovirus and RNA interference systems, respectively, and then applied microarray analysis to identify candidate genes. A total of 100 genes showed inversely correlated differential expression in the two systems. Most of the candidate genes were downregulated by the overexpression of PLU-1/JARID1B, including the MT genes, the tumor suppressor gene BRCA1, and genes involved in the regulation of the M phase of the mitotic cell cycle. Chromatin immunoprecipitation assays confirmed that the metallothionein 1H (MT1H), -1F, and -1X genes are direct transcriptional targets of PLU-1/JARID1B in vivo. Furthermore, the level of trimethyl H3K4 of the MT1H promoter was increased following silencing of PLU-1/JARID1B. Both the PLU-1/JARID1B protein and the ARID domain selectively bound CG-rich DNA. The GCACA/C motif, which is abundant in metallothionein promoters, was identified as a consensus binding sequence of the PLU-1/JARID1B ARID domain. As expected from the microarray data, cells overexpressing PLU-1/JARID1B have an impaired G(2)/M checkpoint. Our study provides insight into the molecular function of the breast cancer-associated transcriptional repressor PLU-1/JARID1B.
Scibetta
Angelo G
AG
Breast Cancer Biology Group, King's College London School of Medicine, 3rd Floor, Thomas Guy House, Guy's Hospital, London SE1 9RT, United Kingdom.
Santangelo
Samantha
S
Coleman
Julia
J
Hall
Debbie
D
Chaplin
Tracy
T
Copier
John
J
Catchpole
Steve
S
Burchell
Joy
J
Taylor-Papadimitriou
Joyce
J
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D042361:Mammary Glands, Human / Q000033:anatomy & histology; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism; D014158:Transcription, Genetic
D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D008668:Metallothionein; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human
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