Expression Pattern Determines Regulatory Logic

Large amounts of effort have been invested in trying to understand how a single genome is able to specify the identity of hundreds of cell types. Inspired by some aspects of Caenorhabditis elegans biology, we implemented an in silico evolutionary strategy to produce gene regulatory networks (GRNs) that drive cell-specific gene expression patterns, mimicking the process of terminal cell differentiation. Dynamics of the gene regulatory networks are governed by a thermodynamic model of gene expression, which uses DNA sequences and transcription factor degenerate position weight matrixes as input. In a version of the model, we included chromatin accessibility. Experimentally, it has been determined that cell-specific and broadly expressed genes are regulated differently. In our in silico evolved GRNs, broadly expressed genes are regulated very redundantly and the architecture of their cis-regulatory modules is different, in accordance to what has been found in C. elegans and also in other systems. Finally, we found differences in topological positions in GRNs between these two classes of genes, which help to explain why broadly expressed genes are so resilient to mutations. Overall, our results offer an explanatory hypothesis on why broadly expressed genes are regulated so redundantly compared to cell-specific genes, which can be extrapolated to phenomena such as ChIP-seq HOT regions.