Calculating transcription factor binding maps for chromatin

Abstract

Current high-throughput experiments already generate enough data for retrieving the DNA sequence-dependent binding affinities of transcription factors (TF) and other chromosomal proteins throughout the complete genome. However, the reverse task of calculating binding maps in a chromatin context for a given set of concentrations and TF affinities appears to be even more challenging and computationally demanding. The problem can be addressed by considering the DNA sequence as a one-dimensional lattice with units of one or more base pairs. To calculate protein occupancies in chromatin, one needs to consider the competition of TF and histone octamers for binding sites as well as the partial unwrapping of nucleosomal DNA. Here, we consider five different classes of algorithms to compute binding maps that include the binary variable, combinatorial, sequence generating function, transfer matrix and dynamic programming approaches. The calculation time of the binary variable algorithm scales exponentially with DNA length, which limits its use to the analysis of very small genomic regions. For regulatory regions with many overlapping binding sites, potentially applicable algorithms reduce either to the transfer matrix or dynamic programming approach. In addition to the recently proposed transfer matrix formalism for TF access to the nucleosomal organized DNA, we develop here a dynamic programming algorithm that accounts for this feature. In the absence of nucleosomes, dynamic programming outperforms the transfer matrix approach, but the latter is faster when nucleosome unwrapping has to be considered. Strategies are discussed that could further facilitate calculations to allow computing genome-wide TF binding maps.