Dense Neural Networks for Predicting Chromatin Conformation

Background: DNA inside eukaryotic cells wraps around histones to form the 11nm chromatin fiber that can further fold into higher-order DNA loops, which may depend on the binding of architectural factors. Predicting how the DNA will fold given a distribution of bound factors, here viewed as a type of sequence, is currently an unsolved problem and several heterogeneous polymer models have shown that many features of the measured structure can be reproduced from simulations. However a model that determines the optimal connection between sequence and structure and that can rapidly assess the effects of varying either one is still lacking. Results: Here we train a dense neural network to solve for the local folding of chromatin, connecting structure, represented as a contact map, to a sequence of bound chromatin factors. The network includes a convolutional filter that compresses the large number of bound chromatin factors into a single 1D sequence representation that is optimized for predicting structure. We also train a network to solve the inverse problem, namely given only structural information in the form of a contact map, predict the likely sequence of chromatin states that generated it. Conclusions: By carrying out sensitivity analysis on both networks, we are able to highlight the importance of chromatin contexts and neighborhoods for regulating long-range contacts, along with critical alterations that affect contact formation. Our analysis shows that the networks have learned physical insights that are informative and intuitive about this complex polymer problem.