title: RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells.
abstract: 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.
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
authors: A Rasim
authors: AR
authors: Barutcu
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA; Department of Biochemistry, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA.
authors: Deli
authors: D
authors: Hong
authors: Program in Systems Biology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA.
authors: Bryan R
authors: BR
authors: Lajoie
authors: Program in Systems Biology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA.
authors: Rachel Patton
authors: RP
authors: McCord
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors: Andre J
authors: AJ
authors: van Wijnen
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA; Department of Biochemistry, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA.
authors: Jane B
authors: JB
authors: Lian
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA; Department of Biochemistry, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA.
authors: Janet L
authors: JL
authors: Stein
authors: Howard Hughes Medical Institute, Program in Systems Biology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA.
authors: Job
authors: J
authors: Dekker
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. Electronic address: anthony.imbalzano@umassmed.edu.
authors: Anthony N
authors: AN
authors: Imbalzano
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA; Department of Biochemistry, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: gary.stein@uvm.edu.
authors: Gary S
authors: GS
authors: Stein
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells
chemical_list: D002843:Chromatin
keywords: Breast cancer; Hi-C; MCF-7; RUNX1; TAD; Topologically associating domain