Taking into account nucleosomes for predicting gene expression

• Assumptions used for bottom-up modeling of gene regulation are critically reviewed.
• Dynamic programming method to calculate TF binding in chromatin is described.
• Model parameterization requires both sequencing methods and life cell imaging.
• TF binding to partially unwrapped nucleosomes needs to be taken into account.
• ATP-dependent action of chromatin remodelers needs to be taken into account.

The eukaryotic genome is organized in a chain of nucleosomes that consist of 145–147 bp of DNA wrapped around a histone octamer protein core. Binding of transcription factors (TF) to nucleosomal DNA is frequently impeded, which makes it a challenging task to calculate TF occupancy at a given regulatory genomic site for predicting gene expression. Here, we review methods to calculate TF binding to DNA in the presence of nucleosomes. The main theoretical problems are (i) the computation speed that is becoming a bottleneck when partial unwrapping of DNA from the nucleosome is considered, (ii) the perturbation of the binding equilibrium by the activity of ATP-dependent chromatin remodelers, which translocate nucleosomes along the DNA, and (iii) the model parameterization from high-throughput sequencing data and fluorescence microscopy experiments in living cells. We discuss strategies that address these issues to efficiently compute transcription factor binding in chromatin.

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