RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells

A. Rasim Barutcu, Deli Hong, Bryan R. Lajoie, Rachel Patton McCord, Andre J. van Wijnen, Jane B. Lian, Janet L. Stein, Job Dekker, Anthony N. Imbalzano, Gary S. Stein

Research output: Contribution to journalArticle

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1389-1397
Number of pages9
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1859
Issue number11
DOIs
StatePublished - Nov 1 2016

Keywords

  • Breast cancer
  • Hi-C
  • MCF-7
  • RUNX1
  • TAD
  • Topologically associating domain

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells'. Together they form a unique fingerprint.

  • Cite this

    Barutcu, A. R., Hong, D., Lajoie, B. R., McCord, R. P., van Wijnen, A. J., Lian, J. B., Stein, J. L., Dekker, J., Imbalzano, A. N., & Stein, G. S. (2016). RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1859(11), 1389-1397. https://doi.org/10.1016/j.bbagrm.2016.08.003