Systematic dissection of co-regulator dependencies reveals conserved and divergent mechanisms of repression

Building on a previously established fluorescent reporter system, we assessed the silencing network across five representative effectors associated with chromatin silencing. We identified a conserved core of factors essential for efficient repression, including histone deacetylation, methylation, and remodeling pathways.

Comparative analyses revealed striking differences between effector silencing kinetics and uncovered distinct requirements for the establishment versus maintenance of repression. Mechanistic dissection demonstrated that its long-term stability depends on the B-box domain and the recruitment of DNA methylation machinery, Polycomb complexes, and additional cofactors, uncovering a critical role of the KRAB-domain architecture in establishing durable epigenetic repression.