RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells
Department of Cell and Developmental Biology; Program in Systems Biology; Department of Biochemistry and Molecular Pharmacology; UMass Metabolic Network
RUNX1 is a transcription factor functioning both as an oncogene and a tumor suppressor in breast cancer. RUNX1 alters chromatin structure in cooperation with chromatin modifier and remodeling enzymes. In this study, we examined the relationship between RUNX1-mediated transcription and genome organization. We characterized genome-wide RUNX1 localization and performed RNA-seq and Hi-C in RUNX1-depleted and control MCF-7 breast cancer cells. RNA-seq analysis showed that RUNX1 depletion led to up-regulation of genes associated with chromatin structure and down-regulation of genes related to extracellular matrix biology, as well as NEAT1 and MALAT1 lncRNAs. Our ChIP-Seq analysis supports a prominent role for RUNX1 in transcriptional activation. About 30% of all RUNX1 binding sites were intergenic, indicating diverse roles in promoter and enhancer regulation and suggesting additional functions for RUNX1. Hi-C analysis of RUNX1-depleted cells demonstrated that overall three-dimensional genome organization is largely intact, but indicated enhanced association of RUNX1 near Topologically Associating Domain (TAD) boundaries and alterations in long-range interactions. These results suggest an architectural role for RUNX1 in fine-tuning local interactions rather than in global organization. Our results provide novel insight into RUNX1-mediated perturbations of higher-order genome organization that are functionally linked with RUNX1-dependent compromised gene expression in breast cancer cells.
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Citation: Biochim Biophys Acta. 2016 Nov;1859(11):1389-1397. doi: 10.1016/j.bbagrm.2016.08.003. Epub 2016 Aug 9. Link to article on publisher's site
Breast cancer, Hi-C, MCF-7, RUNX1, TAD, Topologically associating domain
Biochimica et biophysica acta
Barutcu, A. Rasim; Hong, Deli; Lajoie, Bryan R.; McCord, Rachel Patton; van Wijnen, Andre J.; Lian, Jane B.; Stein, Janet L.; Dekker, Job; Imbalzano, Anthony N.; and Stein, Gary S., "RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells" (2016). Cell and Developmental Biology Publications and Presentations. 195.