A catalytically dead Cas9 (dCas9) has no nuclease activity — it cannot cut DNA. Fused to a chromatin-modifying "effector" domain and guided by a single-guide RNA (sgRNA) complementary to the target locus, it instead deposits or removes epigenetic marks at that site: DNMT3A adds CpG methylation (silencing), TET1 oxidises 5-methylcytosine toward demethylation (activation), and p300 acetylates histone tails (opening chromatin, activation).
dM/dt = k_on · D · (M_target − M) (methylation, per CpG)
dA/dt = k_on · D · (A_target − A) (acetylation, per nucleosome)
E = E_max · [Kᵐ / (Kᵐ + Mⁿ)] · [Aⁿ / (Kᵃ + Aⁿ)] (Hill-type expression)
P(off-target)/s ∝ (1 − specificity/5)
- Effector buttons — choose DNMT3A (methylate → silence), TET1 (demethylate → activate) or p300 (acetylate → activate); each drives M or A toward its target value.
- Specificity — mismatches tolerated by the sgRNA:target duplex; higher tolerance raises the modelled off-target binding rate elsewhere on the helix.
- Delivery efficiency — fraction of complexes that reach and engage the locus; scales the editing rate constant k_on.
- Run/Pause/Reset — advance or restart the stochastic search-and-edit simulation.
This is the mechanism behind experimental epigenetic therapies — e.g. dCas9-DNMT3A silencing a disease allele, or dCas9-p300 reactivating a silenced tumour-suppressor — without ever cutting the genome.