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.

Touch and go: nuclear proteolysis in the regulation of metabolic genes and cancer

“…For instance, a recent integrative genomic analysis of chronic myelogenous leukemia patients treated with Imatinib (a tyrosine kinase inhibitor) showed that NCoR1‐targeted gene signatures were significantly associated with sensitivity to Imatinib. Moreover, the study revealed that Imatinib particularly targeted the NCoR1 governed transcriptome, suggesting that other cancers might also benefit from treatments that stabilize NCoR1 .…”

Pan-Cancer Analyses of the Nuclear Receptor Superfamily

“…However, there are few ChIP-Seq studies for these coactivators and corepressors and largely they have not been analyzed in an unbiased manner. To address this issue we recently undertook an integrative genomics analyses of the NCOR1 cistrome by exploiting ENCODE data(106). Surprisingly, we found that within the NCOR1 cistrome, NR motifs of any type were not the most commonly enriched, compared to other transcription factors.…”

Global gene expression profiles of hematopoietic stem and progenitor cells from patients with chronic myeloid leukemia: the effect of in vitro culture with or without imatinib

“…Trying to understand, at the genomic level, the effects of IM and other tyrosine kinase inhibitors on CML patients, and the molecular nature of TKI resistance, based on gene expression profiles, has been an important goal for several groups. In this regard, significant progress has been made over the last few years . To date, however, and to the best of our knowledge, the genomic changes induced by in vitro administration of IM to pure populations of HPCs have not been reported.…”