ChromWave: Deciphering the DNA-encoded competition between transcription factors and nucleosomes with deep neural networks

Abstract

SummaryTranscription factors (TFs) regulate gene expression by recognising and binding specific DNA sequences. At times, these regulatory elements may be occluded by nucleosomes, making them inaccessible for TF-binding. The competition for DNA occupancy between TFs and nucleosomes, and associated gene regulatory outputs, are important consequences of the cis-regulatory information encoded in the genome. However, these sequence patterns are subtle and remain difficult to interpret. Here, we introduce ChromWave, a deep-learning model that, for the first time, predicts the competing profiles for TF and nucleosomes occupancies with remarkable accuracy. Models trained using short- and long-fragment MNase-Seq data successfully learn the sequence preferences underlying TF and nucleosome occupancies across the entire yeast genome. They recapitulate nucleosome evictions from regions containing “strong” TF binding sites and knock-out simulations show nucleosomes gaining occupancy in the absence of these TFs, accompanied by lateral rearrangement of adjacent nucleosomes. At a local level, models anticipate with high accuracy the outcomes of detailed experimental analysis of partially unwrapped nucleosomes at the GAL4 UAS locus. Finally, we trained a ChromWave model that successfully predicts nucleosome positions at promoters in the human genome. We find that human promoters generally contain few sites at which simple sequence changes can alter nucleosome occupancies and that these positions align well with causal variants linked to DNase hypersensitivity. ChromWave is readily combined with diverse genomic datasets and can be trained to predict any output that is linked to the underlying genomic sequence. ChromWave’s application is limited only by the user’s imagination and availability of training data.

Genomics enters the deep learning era

“…On the other hand, they did not find any motifs that would position nucleosomes by attracting them, suggesting that nucleosome repulsion is the main positioning mechanism. Cakiroglu et al (2021) predicted nucleosome positioning as well as TFBS from the DNA sequence based on results obtained with Micrococcal Nuclease digestion treatment (MNase-seq, Cakiroglu et al (2021) ). The model was able to reproduce the competition between nucleosomes and TFs for binding on the DNA.…”