Phase separation as high-order catalyst

Abstract

The long-distance communication between multiple cis-regulatory elements (CREs), the self-limiting size and lifetime of regulatory condensates, are two puzzling phenomena in biology. To reconcile these puzzles, we introduce the concept of higher-order catalysis into chromatin-mediated reactions. Essentially, multi-way contact between the CREs defines a transition state that is required for the downstream cascade of chemical reactions. The entropic penalty of chromatin reorganization sets a high activation barrier to enter this transition state. Phase separation of trans-acting agents induced by the CREs reduces this barrier and stabilizes the transition state via forming a regulatory condensate. The downstream reaction then pays back energy to dissolve the condensate and resets the agents to a metastable single-phase state. Accelerating the reactions without consuming agents or changing their state, the cycled phase transitions construct a higher-order catalyst or super-enzyme that is beyond the form of a single molecule. We discuss how chromatin employs such super-enzymes to catalyze higher-order reactions mediated by itself.