Genome wide analysis of YBX1-mediated redistribution of JMJD6 in ER+ breast cancer cells

Abstract The molecular mechanisms by which cancer cells proliferate under diminished ER expression leading to intrinsic and acquired resistance to endocrine therapy remain incompletely understood. Here, we identify a previously unrecognized transcriptional axis centred on JMJD6 and YBX1 that cooperatively reprograms chromatin, redistributes enhancer engagement and sustains tumor proliferation when JMJD6 levels are elevated (JOE cells). Through proximity ligation, ChIP-reChIP assays, KO-based ablation experiments, and genome-wide profiling, we demonstrate that YBX1 is required for JMJD6 enrichment at regulatory sites. ∼20% of JMJD6 and YBX1 peaks physically superimpose, and remaining peaks are contained within a neighbourhood of ±50kb. A shared extended binding site (EBS) containing (i) flanking poly-A/poly-T tracts; (ii) a canonical YBX1 recognition sequence; and (iii) a second complementary motif enriched for zinc-finger proteins defines JMJD6–YBX1 regulated enhancers. Histone modification landscapes in JMJD6 overexpressing cells supported the presence of a transcription permissive chromatin. Further, JMJD6/YBX1 siRNA and overexpression analysis in MCF7 cells identified estrogen and interferon gamma signalling as prominent pathways. The most compelling observation was that ER loss was transcriptional in JOE cells and was accompanied by the emergence of JMJD6–YBX1 enhancer sites at alternate genomic positions relative to canonical ER–JMJD6 sites described in estrogen-stimulated cells. These findings offer a mechanistic insight into earlier reports from our group showing that high JMJD6 with YBX1 suppresses ER expression and this could promote endocrine resistance. Competing Interest Statement The authors have declared no competing interest.