Autonomous Reshaping of Expression Landscapes by DNA Methylation

Abstract

DNA methylation is usually treated as an epigenetic memory mark: transcriptional history is written into regulatory DNA and later stabilizes a chosen cell identity. This picture explains persistence, but it makes memory passive. Here we show that the same promoter-level coupling required for methylation memory can instead turn methylation into an internal control variable for regulatory dynamics. Transcription-factor occupancy protects regulatory DNA from methylation, while methylation shifts later transcription-factor binding thresholds. Under time-scale separation, this reciprocal loop separates into fast expression dynamics conditioned on methylation and a slow methylation flow written by expression. Minimal promoter, self-activation, and fate-toggle models show that this feedback does more than preserve a past state: it autonomously reshapes the expression landscape. In a methylation-coupled toggle, the preferred expression state can move continuously through single-well drift, allowing commitment without first entering a multiwell regime. Stochastic simulations further show that evolving methylation reduces fate reversals relative to a frozen landscape, making weak early expression bias more predictive of later fate. These results recast DNA methylation from a downstream stabilizer of cell identity into a slow dynamical coordinate that can help determine how regulatory states are chosen.