MaaD-TAD: an all-atom model of the duplicated PRAMEF/HNRNPCL chromatin domain built from sequence homology
In the nucleus, the placement of genes in the 3D fold of DNA affects how they function. Models of this fold use two kinds of data: contact maps constructed from Hi-C, and nucleosome maps showing where DNA is wound around nucleosomes. Over evolution, sections of the genome were copied, creating near-identical regions. Reads from these regions cannot be assigned to one copy and are discarded, leaving "void regions" in both maps. We tested MaaD-TAD, a pipeline that models topologically associating domains (TADs) at the atomic level, on the PRAMEF/HNRNPCL locus on human chromosome 1. This challenging locus spans 652 kb, with only 15% of its nucleosome positions known and most contact data missing. To test our hypothesis that copies with similar sequence lie close in space, i.e. homology as a surrogate for proximity, we constructed a map of sequence homology in place of Hi-C and used CSynth to fold it into a 3D path. We then lengthened the path to fit a chromatin fibre, and refined the model by adding cohesin complexes, which stabilize chromatin structure. Cohesin is a ring-shaped protein complex through which a loop of chromatin is threaded; the loop is commonly anchored by CTCF proteins bound on either leg. Using known databases, we placed CTCF sites in our model and joined three to their copies with cohesin rings; in each pair the sites face each other, as loop anchors do. The final model holds 3,359 nucleosomes and about 55 million atoms. Micro-C, an advanced, higher-resolution form of Hi-C, provided data on two other duplicated regions that support our hypothesis: matching copies touched 1.2 to 1.9 times more often than expected. Our approach provides a novel method to reconstruct DNA regions with absent contact data and, to our knowledge, the first all-atom model of a complete TAD.