# Enhancer–Promoter Looping as Causal

Enhancers regulate genes, but continuous physical contact throughout every transcriptional burst is contradicted by native-locus measurements within their detection limits.

The registered primary SC3 necessity gate is Β: partial mechanistic plausibility is capped at Γ, then one endogenous-prediction falsification pattern lowers it one rung. Native Sox2 simultaneous imaging and orthogonal neural Shh/estrogen distance findings oppose the universal sustained-contact prediction within detection limits. This is neither proof that brief contacts never occur nor a denial of causal enhancer function. Exact index additionally restricts synthetic SC2 sufficiency to Γ; broad SC4 graded frequency remains Γ because its strongest controlled tests use synthetic tethers/landscapes and snapshot or inferred kinetics.

Mammalian native loci are the gate; engineered reporters, purified systems and two Drosophila comparators are explicitly outside that crossing. Brain versus limb enhancers, quiescent macrophages versus ESC maintenance, genomic distance and activation history are defined before interpreting response. No responder-only population is invented.