Abstract

The mammalian genome is packed tightly in the nucleus of the cell. This packing is primarily facilitated by histone proteins and results in an ordered organization of the genome in chromosome territories that can be roughly divided in heterochromatic and euchromatic domains. On top of this organization several distinct gene regulatory elements on the same chromosome or other chromosomes are thought to dynamically communicate via chromatin looping. Advances in genome-wide technologies have revealed the existence of a plethora of these regulatory elements in various eukaryotic genomes. These regulatory elements are defined by particular in vitro assays as promoters, enhancers, insulators, and boundary elements. However, recent studies indicate that the in vivo distinction between these elements is often less strict. Regulatory elements are bound by a mixture of common and lineage-specific transcription factors which mediate the long-range interactions between these elements. Inappropriate modulation of the binding of these transcription factors can alter the interactions between regulatory elements, which in turn leads to aberrant gene expression with disease as an ultimate consequence. Here we discuss the bi-modal behavior of regulatory elements that act in cis (with a focus on enhancers), how their activity is modulated by transcription factor binding and the effect this has on gene regulation.

Highlights

  • Expression of genes is to a large extent directed by regulatory sequences within the promoters of genes

  • A significant proportion of genome-wide association studies (GWAS) single nucleotide polymorphisms (SNPs) overlap with B, T, and ES cell enhancers (Teng et al, 2011), multiple sclerosis associated regions are located in chromatin regions that are active in B-cells (Disanto et al, 2012) and 80% of the colorectal cancer risk SNPs overlap with colon crypt enhancer marks (Akhtar-Zaidi et al, 2012)

  • PROSPECTS Knowledge regarding enhancers and enhancer function has exploded in the past decades

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Summary

INTRODUCTION

Expression of genes is to a large extent directed by regulatory sequences within the promoters of genes. The first enhancers described were SV40 viral repeat sequences that are able to boost expression of a rabbit β-globin construct (Banerji et al, 1981). The first attempts to identify enhancers on a genome-wide scale did not depend on DNaseI but involved enhancers traps (Hamada, 1986) In this method, a selectable reporter gene driven by an enhancer dependent promoter is randomly integrated in to the genome. Subsequent validation of enhancer activity can be done in vitro by transiently transfecting luciferase reporter constructs in cell lines or in vivo using reporter constructs in transgenic animals.

Palstra and Grosveld
Findings
CONCLUSIONS AND FUTURE PROSPECTS
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