The epigenetic landscape of living cells is dynamic and heterogeneous. To track these changes with high temporal resolution, fluorescent biosensors can be powerful tools. We aimed to use the split-Venus system to monitor the dynamic changes in DNA methylation levels at the major satellite repeat regions. While the individual components of the biosensor showed specificity for their targets, key control experiments demonstrated that the combined biosensor constructs failed to respond to global DNA methylation changes. Specifically, the high intrinsic affinity of the split-Venus halves appeared to drive strong false-positive signal. The observed non-specific complementation highlights a critical limitation of split fluorophore systems and calls into question their applicability to track dynamic processes.