title: Integrative genomic analysis in K562 chronic myelogenous leukemia cells reveals that proximal NCOR1 binding positively regulates genes that govern erythroid differentiation and Imatinib sensitivity.
abstract: To define the functions of NCOR1 we developed an integrative analysis that combined ENCODE and NCI-60 data, followed by in vitro validation. NCOR1 and H3K9me3 ChIP-Seq, FAIRE-seq and DNA CpG methylation interactions were related to gene expression using bootstrapping approaches. Most NCOR1 combinations (24/44) were associated with significantly elevated level expression of protein coding genes and only very few combinations related to gene repression. DAVID's biological process annotation revealed that elevated gene expression was uniquely associated with acetylation and ETS binding. A matrix of gene and drug interactions built on NCI-60 data identified that Imatinib significantly targeted the NCOR1 governed transcriptome. Stable knockdown of NCOR1 in K562 cells slowed growth and significantly repressed genes associated with NCOR1 cistrome, again, with the GO terms acetylation and ETS binding, and significantly dampened sensitivity to Imatinib-induced erythroid differentiation. Mining public microarray data revealed that NCOR1-targeted genes were significantly enriched in Imatinib response gene signatures in cell lines and chronic myelogenous leukemia (CML) patients. These approaches integrated cistrome, transcriptome and drug sensitivity relationships to reveal that NCOR1 function is surprisingly most associated with elevated gene expression, and that these targets, both in CML cell lines and patients, associate with sensitivity to Imatinib.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Long
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: van den Berg
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Russell
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA pksingh3@buffalo.edu.
authors.forename: Prashant K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA Sebastiano.Battaglia@RoswellPark.org.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Battaglia
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA Moray.Campbell@roswellpark.org.
authors.forename: Moray J
authors.initials: MJ
authors.lastname: Campbell
mesh_terms: D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D023281:Genomics; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020014:K562 Cells; D056971:Nuclear Receptor Co-Repressor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D000068877:Imatinib Mesylate