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. 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. This suggests 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.

The enigmatic role of RUNX1 in female‐related cancers – current knowledge & future perspectives

“…). Intriguingly, this is in line with very recent findings depicting RUNX1 as an architectural genome regulator of local (rather than global) chromatin interactions that might become dysregulated in cancer . It is important to note, however, that this is not the first time the RUNX genes have been associated with the oestrogen/ER signalling, where an antagonist relationship with RUNX2 and RUNX3 has been proposed.…”

Higher order genomic organization and regulatory compartmentalization for cell cycle control at the G1/S‐phase transition

“…This question has been the focus of studies on subnuclear organization (Cremer & Cremer, ; Zaidi et al, ). Emerging evidence using genome‐wide high‐resolution chromosome conformation capture (Hi‐C) technologies indicates that non‐random higher‐order organization of genes into structural domains supports regulatory activities involving non‐contiguous sequences that influence transcription (Barutcu et al, ; Belton et al, ; Ching, Ahmed, Boutros, Penn, & Bazett‐Jones, ; Dekker, Marti‐Renom, & Mirny, ; Hamdi et al, ; Lieberman‐Aiden et al, ; Martin et al, ; Matheson & Kaufman, ; Mifsud et al, ; Rowley & Corces, ; Tjong et al, ; Wang et al, ).…”

Identification of tRNA‐derived small RNA (tsRNA) responsive to the tumor suppressor, RUNX1, in breast cancer

“…Furthermore, ectopic overexpression of RUNX1 in aggressive breast cancer cells reduced migration, invasion, and stemness, as well as inhibited tumor growth in mice as determined by reduced xenograft size in the mammary fat pad (Hong, Fritz, Finstad et al, ). Moreover, published reports indicate that RUNX1 interacts with TP53 (Wu, Ozaki, Yoshihara, Kubo, & Nakagawara, ), ETS1 (Shrivastava et al, ), and regulates chromatin and global gene expression profiles in breast cancer (Barutcu et al, ). Yet the tumor suppressor‐like molecular mechanisms of RUNX1 in breast cancer remain elusive.…”