Deciphering the multi-scale, quantitative cis-regulatory code

Uncovering the cis-regulatory code that governs when and how much each gene is transcribed in a given genome and cellular state remains a central goal of biology. Here, we discuss major layers of regulation that influence how transcriptional outputs are encoded by DNA sequence and cellular context. We first discuss how transcription factors bind specific DNA sequences in a dosage-dependent and cooperative manner and then proceed to the cofactors that facilitate transcription factor function and mediate the activity of modular cis-regulatory elements such as enhancers, silencers, and promoters. We then consider the complex and poorly understood interplay of these diverse elements within regulatory landscapes and its relationships with chromatin states and nuclear organization. We propose that a mechanistically informed, quantitative model of transcriptional regulation that integrates these multiple regulatory layers will be the key to ultimately cracking the cis-regulatory code. The cis-regulatory code dictates how DNA sequence controls quantitative transcription levels of each gene depending on cellular context. Kim and Wysocka review progress and challenges in understanding the layers of this code, from transcription factor binding to cofactor recruitment and ultimately cis-regulatory element specificity and function within complex regulatory landscapes.