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.

Chromatin organization drives the search mechanism of nuclear factors.

Nuclear factors rapidly scan the genome for their targets, but the role of nuclear organization in such search is uncharted. Here we analyzed how multiple factors explore chromatin, combining live-cell single-molecule tracking with multifocal structured illumination of DNA density. We find that factors displaying higher bound fractions sample DNA-dense regions more exhaustively.

The needle and the haystack: single molecule tracking to probe the transcription factor search in eukaryotes.

Transcription factors (TFs) regulate transcription of their target genes by identifying and binding to regulatory regions of the genome among billions of potential non-specific decoy sites, a task that is often presented as a 'needle in the haystack' challenge. The TF search process is now well understood in bacteria, but its characterization in eukaryotes needs to account for the complex organization of the nuclear environment. Here we review how live-cell single molecule tracking is starting to shed light on the TF search mechanism in the eukaryotic cell and we outline the future challenges to tackle in order to understand how nuclear organization modulates the TF search process in physiological and pathological conditions.