Rethinking chromatin accessibility: from compaction to dynamic interactions

The genome is traditionally divided into condensed heterochromatin and open euchromatin. However, recent findings challenge this binary classification and the notion that chromatin condensation solely governs the accessibility of transcription factors (TFs) and, consequently, gene expression. Instead, chromatin accessibility is emerging as a factor-specific property that is influenced by multiple determinants. These include the mobility of the chromatin fiber, the capacity of TFs to engage repeatedly with it through multivalent interactions, and the four-dimensional organization of its surrounding diffusible space. Unraveling the molecular and biophysical principles that render a genomic target truly accessible remains a significant challenge, but innovative methods for locally perturbing chromatin, coupled with microscopy techniques that offer single-molecule sensitivity, provide an exciting experimental playground to test new hypotheses.