Disentangling the many layers of eukaryotic transcriptional regulation - PubMed (original) (raw)

Review

Disentangling the many layers of eukaryotic transcriptional regulation

Katherine M Lelli et al. Annu Rev Genet. 2012.

Abstract

Regulation of gene expression in eukaryotes is an extremely complex process. In this review, we break down several critical steps, emphasizing new data and techniques that have expanded current gene regulatory models. We begin at the level of DNA sequence where cis-regulatory modules (CRMs) provide important regulatory information in the form of transcription factor (TF) binding sites. In this respect, CRMs function as instructional platforms for the assembly of gene regulatory complexes. We discuss multiple mechanisms controlling complex assembly, including cooperative DNA binding, combinatorial codes, and CRM architecture. The second section of this review places CRM assembly in the context of nucleosomes and condensed chromatin. We discuss how DNA accessibility and histone modifications contribute to TF function. Lastly, new advances in chromosomal mapping techniques have provided increased understanding of intra- and interchromosomal interactions. We discuss how these topological maps influence gene regulatory models.

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Figures

Figure 1

Figure 1

Overview of eukaryotic gene regulation. Within the nucleus of a cell, chromosomes occupy defined spatial regions called territories. Interactions between adjacent territories can correlate with transcriptionally active chromatin in transcription factories or silenced chromatin in Polycomb Group (PcG) bodies. Posttranslational modification of transcription factors (TFs), such as phosphorylation (P), can influence nuclear import (dashed arrows) through nuclear pore complexes (NPCs) in response to extracellular signals. Posttranslational modifications of histones, such as methylation (Me), can also correlate with the transcriptional state of associated genes. The position of nucleosomes can restrict access of TFs by occluding binding sites (colored rectangles). Lastly, TF recognition of specific binding sites, either as monomers or as a part of a complex with other proteins, also contributes to proper recruitment or release of RNA polymerase from the transcriptional start site (TSS). Abbreviations: K, kinase; Ph, phosphatase.

Figure 2

Figure 2

_Cis_-regulatory module (CRM) assembly and cooperative DNA-binding models. This image depicts three different models of CRM assembly and related cooperativity mechanisms. (a) The enhanceosome model requires strict modular cooperativity between all transcription factors (TFs) (129, 131). (b) In contrast, the flexibility of the Billboard and TF Collective models permits different cooperativity mechanisms to control CRM assembly. (c) In the case of DNA allostery, interactions between the DNA sequence and the TF can facilitate conformational changes in the TF that result in the recruitment of different regulatory complexes (rounded rectangles) in a sequence-specific manner (108). (e) Classical cooperativity uses protein-protein interactions between TFs to facilitate cooperative binding. These types of cooperative interactions help to increase TF DNA-binding specificity by restricting recruitment to dimeric sites (A+B). In the case of latent specificity, direct protein-protein interactions alter binding specificities so that TFs recognize novel composite sites (A’B’) (161). (f) Lastly, collaborative competition between TFs and nucleosomes can lead to cooperative binding when the binding of one TF provides access for another TF to bind a neighboring site (114, 120, 167).

Figure 3

Figure 3

Different types of long-range interactions. (a) Interactions between elements in a single locus. Tissue-specific conformations of elements within the Distalless (Dll) locus correlate with gene activity. In the thorax, where Dll is expressed, the locus is more compact, with several regions interacting over long distances. However, in the abdomen, where Dll is repressed, the locus adapts a more extended conformation, and no interactions are observed between regulatory elements (2). (b) Interactions between elements in a gene complex. In Drosophila three gene complexes, antennapedia (ANT-C), bithorax (BX-C), and NK homeobox (NK-C), create foci of extensive intracomplex interactions when repressed by polycombs called Polycomb group (PcG) bodies (9). Additionally, intercomplex interactions suggest that PcG bodies can encompass more than one complex (9). However, PcG bodies containing all three complexes have not been observed (9). During vertebrate development, Hox genes cluster according to gene activity (125). In the forebrain, where none of the Hox genes are expressed, chromosome conformation capture-on-chip analysis indicates that all members of the complex group together (red). However, in trunk regions Hox genes adopt a bimodal distribution in which all the active genes (green) are found in one cluster and the inactive ones (red) interact within a different cluster (125). Furthermore, this three-dimensional organization correlates with collinear gene activation (125). (c) Interactions between chromosomes. During odorant receptor choice in mouse neurons, trans interactions can occur between the H enhancer and genes on different chromosomes (94). In this case, we have depicted interactions between the H enhancer on chromosome 14 and the M50 gene on chromosome 7 (94). Additionally, interactions between _Klf1_-regulated genes (green) on different chromosomes have been observed in erythroid cells (151). This colocalization of active genes constitutes a transcription factory.

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