Multiple layers of complexity in cis‐regulatory regions of developmental genes

Abstract

Genomes contain the necessary information to ensure that genes are expressed in the right place, at the right time, and with the proper rate. Metazoan developmental genes often possess long stretches of DNA flanking their coding sequences and/or large introns which contain elements that influence gene expression. Most of these regulatory elements are relatively small and can be studied in isolation. For example, transcriptional enhancers, the elements that generate the expression pattern of a gene, have been traditionally studied with reporter constructs in transgenic animals. These studies have provided and will provide invaluable insights into enhancer evolution and function. However, this experimental approach has its limits; often, enhancer elements do not faithfully recapitulate native expression patterns. This fact suggests that additional information in cis-regulatory regions modulates the activity of enhancers and other regulatory elements. Indeed, recent studies have revealed novel functional aspects at the level of whole cis-regulatory regions. First, the discovery of ''shadow enhancers.'' Second, the ubiquitous interactions between cis-regulatory elements. Third, the notion that some cis-regulatory regions may not function in a modular manner. Last, the effect of chromatin conformation on cis-regulatory activity. In this article, I describe these recent findings and discuss open questions in the field.

Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development

“…It is now well established that dynamically expressed genes often contain multiple enhancers, some of which direct overlapping, or at least very similar, patterns of expression. This phenomenon has been reported for a number of endothelial-expressed genes, including Mef2c, Tal1, and Kdr (18,24). Some arterial β-gal expression is detectable in Dll4…”

Regulatory Logic of Pan-Neuronal Gene Expression in C. elegans

“…Seemingly redundant regulatory elements, driving similar expression in the same cells or tissues of an animal have been documented in the literature for numerous developmental patterning genes (Frankel, 2012). In a number of these cases, the redundant regulatory elements have been coined “shadow enhancers” (Hong et al, 2008; Lagha et al, 2012).…”

A Gli silencer is required for robust repression of gremlin in the vertebrate limb bud

“…Shadow elements are defined by the genetic interactions of two genetically defined CRMs (Frankel, 2012) and further genetic studies involving multiple Glibound elements would be required to determine if the Gli CRM is functioning as a shadow repressor of Grem1. Our study, focused exclusively on a single Gli CRM, is the first to address the potential genetic role that multiple Gli-bound CRMs play in regulating transcription.…”