How to tune an enhancer

Abstract

Every cell’s genome contains two main classes of functional DNA. The best understood type of DNA sequence, which was also the first to be discovered, is that which encodes RNA and protein products via the near-universal “genetic code” (1). A more mysterious but equally important class of functional DNA is cis-regulatory sequence, which does not have a physical product but, instead, encodes the conditions under which a particular RNA will be produced. Cis-regulatory DNA sequences are the primary (although not the only) determinant of gene expression: Not only the rate of RNA production but also the timing, spatial patterning, and environmental control of every gene’s activity are largely controlled by these DNA sequences, which are usually in the general vicinity of the gene they regulate. These DNA segments (often called enhancers) have no enzymatic activity on their own, but act as scaffolds for large complexes of proteins and RNAs that directly control the activity of a gene’s promoter, sometimes over distances of 1 million base pairs or more (2). Transcription factors (TFs), key protein regulators of gene expression, bind DNA in a sequence-specific manner, which means that the nature of the complex assembled at a given enhancer at a given time depends on its DNA sequence (cis information), in conjunction with the set of TFs present and active in the cell …