The Causes and Consequences of Spatial Organization of the Genome in Regulation of Gene Expression

Abstract

Regulation of gene expression in time, space and quantity is orchestrated by the functional interplay of cis-acting elements and trans-acting factors. Our current view postulates that transcription factors recognize enhancer DNA and read the transcriptional regulatory code by cooperative DNA binding to specific DNA motifs, thus instructing the recruitment of transcriptional regulatory complexes forming a plethora of higher-ordered multi-protein-DNA and protein-protein complexes. Here, we reviewed the formation of multi-dimensional chromatin assemblies implicated in gene expression with emphasis on the regulatory role of enhancer hubs as coordinators of stochastic gene expression. Enhancer hubs contain many interacting regulatory elements and represent a remarkably dynamic and heterogeneous network of multivalent interactions. A functional consequence of such complex interaction networks could be that individual enhancers function synergistically to ensure coordination, tight control and robustness in regulation of expression of spatially connected genes. In this review, we discuss fundamental paradigms of such inter- and intra- chromosomal associations both in the context of immune-related genes and beyond.

Keywords: chromatin; enhancer hubs; enhancers; regulation of transcription; stochastic expression; transcription factors.

Figure 1

(A) A model depicting the virus infection-induced NRC-IFNβ interchromosomal interactions. In uninfected cells, the IFNB and NRC loci are well separated. Virus infection induces the nuclear localization of NF-κB, which binds cooperatively with ThPOK to appropriately spaced binding sites at NRCs (right part). While bound to NRCs, ThPOK oligomerizes to reach to a single IFNβ allele resulting in physical proximity of the NRCs-bound NF-κB with the IFNβ enhancer triggering enhanceosome assembly and subsequently activation of the IFNβ gene. (B) A model depicting the assembly of enhancer hubs and transcriptional condensates. In resting cells enhancers and transcriptional regulators are diffused in the nucleus. Upon cell activation transcriptional condensates bearing enhancers, promoters and regulators are formed as a result of liquid-liquid phase separation. Components are highly concentrated within the condensates.