The study investigates the mechanism of estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping. The authors used an "omics" approach, combining transcriptome, methylome, and estrogen receptor alpha (ESR1)-binding datasets from normal breast epithelia and breast cancer cells. They identified 11 large repressive zones, including a 14-gene cluster on chromosome 16p12.2. In normal cells, estrogen signaling induced the transient formation of multiple DNA loops in this region, bringing distant loci to focal ESR1-docking sites for coordinated repression. However, this plasticity was reduced in breast cancer cells, where the establishment of permanent DNA loop structures was observed. The study also found that DNA methylation and repressive chromatin modifications, such as H3K27me3, were associated with the repressed regions. The findings challenge the traditional view that one repressor unit corresponds to one silent gene, suggesting that long-range epigenetic silencing (LRES) can occur in large chromosomal regions and be regulated by ESR1-dependent DNA looping.The study investigates the mechanism of estrogen-mediated epigenetic repression of large chromosomal regions through DNA looping. The authors used an "omics" approach, combining transcriptome, methylome, and estrogen receptor alpha (ESR1)-binding datasets from normal breast epithelia and breast cancer cells. They identified 11 large repressive zones, including a 14-gene cluster on chromosome 16p12.2. In normal cells, estrogen signaling induced the transient formation of multiple DNA loops in this region, bringing distant loci to focal ESR1-docking sites for coordinated repression. However, this plasticity was reduced in breast cancer cells, where the establishment of permanent DNA loop structures was observed. The study also found that DNA methylation and repressive chromatin modifications, such as H3K27me3, were associated with the repressed regions. The findings challenge the traditional view that one repressor unit corresponds to one silent gene, suggesting that long-range epigenetic silencing (LRES) can occur in large chromosomal regions and be regulated by ESR1-dependent DNA looping.