A looping code for chromatin looping?

Chromatin looping between cis-regulatory elements is essential for precise developmental gene expression, but the underlying mechanisms are poorly understood. Here, we show that high GAF is required for chromatin looping between Polycomb Response Elements and gene regulation, while PRC1 itself and the H3K27me3 repressive mark are both dispensable. However, GAF alone cannot establish loops without additional factors, and orthologous PRE sequences can surprisingly rescue looping, while unrelated PREs with similar GAF levels cannot. This indicates that looping specificity depends on both GAF levels and compatible factor combinations at loop anchors.