Transcription factor binding at enhancers: shaping a genomic regulatory landscape in flux

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.

Keywords: chromatin looping; cis-regulation; enhancer; transcription; transcription factor.

FIGURE 1

The genome is organized in transcription factor mediated chromosome loops. Structural transcription factors like CTCF and cohesin (green rectangles and black ring) co-operate to partition the genome in looped domains. Depending on the location of the anchor points of these looped domains, enhancers are either excluded from a target gene’s domain, effectively blocking activation (top right), or included in the target gene’s topological domain (bottom). Tissue specific and ubiquitous transcription factors (pentagons) either induce enhancer–promoter communication via a chromatin loop (bottom right) or keep enhancers in a silent/poised state (bottom left). Rectangles depict CTCF, the black ring represents the cohesin complex, pentagons depict enhancer bound transcription factors and ovals depict components of the pre-initiation complex. Size of the icons depicts strength of binding or activity.

FIGURE 2

Model depicting how sequence variation in distal regulatory elements might influence phenotypes or disease states. A phenotype associated SNP rsXXXXX is located in an enhancer for gene X. The T allele of rsXXXXX binds a transcription factor (the gray pentagon) with high affinity which allows for chromatin loop formation and proper activation of gene X resulting in normal development (left, green arrows). The C allele of rsXXXXX binds the transcription factor with a reduced affinity (light gray pentagon with dashed border) which leads to a less efficient enhancer, absence/reduction of looping and diminished expression of gene X resulting in aberrant or deviated development (right, red arrows). Note that gene Y is located in between the enhancer and gene X and is not regulated by the enhancer. Pentagons depict enhancer bound transcription factors and ovals depict components of the pre-initiation complex. Size of the icons depicts strength of binding or activity.