(A) Four states for a two-gene reporter, where the first letter (yellow) represents the mCitrine state and the second letter (red) represents mCherry state, as either active (A) or silent (S). Arrows represent the rates at which each gene is turned on or off. (B) During KRAB recruitment, cells transition from both genes active (AA) to both gene silent (SS), with mCitrine silencing first (SA intermediate state). The silencing rates of KRAB at the nearby pEF-mCitrine (ks_KRAB ) and pRSV-mCherry (ks_KRAB(d), where d is the distance between the pEF and pRSV promoters) dominate over the activation rates of promoters (ka1 , ka2 ) and insulators (ka_ins(d),where here d is the distance between the core insulator and a nearby promoter). (C) During HDAC4 recruitment, silencing of mCitrine (AA to SA) is driven by the silencing rate of HDAC4 (ks_HDAC4 ), while silencing of mCherry (SA to SS) is driven by background silencing rate (kbs2 ) due to PRC2. Both the pRSV promoter (ka2 ) and insulator reactivation rates (ka_ins) can compete with pRSV-mCherry silencing. (D) Before CR recruitment (no dox), pEF as well as insulators can act from a distance on pRSV (ka1(d), ka_ins(d)) preventing background silencing of mCherry (kbs2 ). (E) KRAB can act on genes over a long distance (ks(d)), silencing both mCitrine and mCherry, while the range of HDAC4 silencing is much smaller (ks ), only directly affecting mCitrine. (F) In the absence of CR recruitment, promoters can activate themselves (ka1 , ka2 ), and maintain activity of genes at a distance (ka1(d), ka2 (d)). In CHO-K1, pRSV is weaker than in K562. (G) When genes are silenced, their promoters cannot act on neighboring genes, instead only reactivate themselves (ka1 , ka2 ). (H) The core element of the cHS4 insulator can maintain activity of the nearby genes and drive reactivation after CR-mediated silencing (ka_ins(d)). (I) Reactivation after silencing is driven by gene activation rates (ka1 , ka2 ) and core cHS4 insulators (ka_ins(d)) if present. In CHO-K1 cells where pEF is stronger than pRSV, mCitrine reactivates first followed by mCherry (left). However, in K562 where both promoters are equally strong, either gene can reactivate first (right).