Interphase chromatin as a self-returning random walk: Can DNA fold into liquid trees?*

We introduce a self-returning random walk to describe the structure of interphase chromatin. Based on a simple folding algorithm, our de novo model unifies the high contact frequency discovered by genomic techniques, and the high structural heterogeneity revealed by imaging techniques, which two chromatin properties we theoretically prove to be irreconcilable within a fractal polymer framework. Our model provides a holistic view of chromatin folding, in which the topologically associated domains are liquid-tree-like structures, linked and isolated by stretched out, transcriptionally active DNA to form a secondary structure of chromatin that further folds into a “3D forest” under confinement. The model pivots an unprecedentedly wide array of experimental observations and suggests the existence of a universal chromatin folding principle. Based on a global folding parameter, the model reveals a unique structure-function relation of chromatin, which is abnormal from a polymer point of view but explains some experimental observations of how chromatin responses to stress.