Motif models proposing independent and interdependent impacts of nucleotides are related to high and low affinity transcription factor binding sites in Arabidopsis

Anton V Tsukanov; Victoria V Mironova; Victor G Levitsky

doi:10.3389/fpls.2022.938545

Motif models proposing independent and interdependent impacts of nucleotides are related to high and low affinity transcription factor binding sites in Arabidopsis

Front Plant Sci. 2022 Jul 28:13:938545. doi: 10.3389/fpls.2022.938545. eCollection 2022.

Authors

Anton V Tsukanov¹, Victoria V Mironova^{1

2}, Victor G Levitsky^{1

3}

Affiliations

¹ Department of Systems Biology, Institute of Cytology and Genetics, Novosibirsk, Russia.
² Department of Plant Systems Physiology, Radboud Institute for Biological and Environmental Sciences (RIBES), Radboud University, Nijmegen, Netherlands.
³ Department of Natural Science, Novosibirsk State University, Novosibirsk, Russia.

Abstract

Position weight matrix (PWM) is the traditional motif model representing the transcription factor (TF) binding sites. It proposes that the positions contribute independently to TFs binding affinity, although this hypothesis does not fit the data perfectly. This explains why PWM hits are missing in a substantial fraction of ChIP-seq peaks. To study various modes of the direct binding of plant TFs, we compiled the benchmark collection of 111 ChIP-seq datasets for Arabidopsis thaliana, and applied the traditional PWM, and two alternative motif models BaMM and SiteGA, proposing the dependencies of the positions. The variation in the stringency of the recognition thresholds for the models proposed that the hits of PWM, BaMM, and SiteGA models are associated with the sites of high/medium, any, and low affinity, respectively. At the medium recognition threshold, about 60% of ChIP-seq peaks contain PWM hits consisting of conserved core consensuses, while BaMM and SiteGA provide hits for an additional 15% of peaks in which a weaker core consensus is compensated through intra-motif dependencies. The presence/absence of these dependencies in the motifs of alternative/traditional models was confirmed by the dependency logo DepLogo visualizing the position-wise partitioning of the alignments of predicted sites. We exemplify the detailed analysis of ChIP-seq profiles for plant TFs CCA1, MYC2, and SEP3. Gene ontology (GO) enrichment analysis revealed that among the three motif models, the SiteGA had the highest portions of genes with the significantly enriched GO terms among all predicted genes. We showed that both alternative motif models provide for traditional PWM greater extensions in predicted sites for TFs MYC2/SEP3 with condition/tissue specific functions, compared to those for TF CCA1 with housekeeping functions. Overall, the combined application of standard and alternative motif models is beneficial to detect various modes of the direct TF-DNA interactions in the maximal portion of ChIP-seq loci.

Keywords: ChIP-seq data analysis; de novo motif search; heterogeneity of transcription factor binding sites; high and low affinity of transcription factor binding sites; standard and alternative motif recognition models.