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How genes are switched on and off at the correct time and in the correct place is a crucial and enduring question for researchers. Advances in our ability to characterize protein–DNA and protein–protein interactions, the dynamics of chromatin structure and transcriptional output under different conditions have substantially enhanced understanding in this area. The articles in this series consider the range of levels at which transcription is controlled, the molecules involved and how the modes of regulation are adapted to particular types of gene or developmental contexts.
In this Review, Gasperini, Tome and Shendure discuss the evolving definitions of transcriptional enhancers, as well as diverse modern experimental tools to identify them. The authors describe how these diverse mindsets and methods provide differing but complementary insights into enhancers, each with notable strengths and caveats. They discuss how such views and approaches might be combined in a comprehensive catalogue of functional enhancers.
Activating transcriptional regulatory elements have traditionally been categorized into promoters, which define transcription start sites, and enhancers, which act distally to stimulate transcription. In this Review, Andersson and Sandelin discuss the latest findings from methodologies for profiling and testing transcriptional regulatory elements at scale. They explain how the data support an updated, nuanced model that accounts for the numerous overlapping molecular properties of promoters and enhancers.
Chromatin accessibility comprises the positions, compaction and dynamics of nucleosomes, as well as the occupancy of DNA by other proteins such as transcription factors. In this Review, the authors discuss diverse methods for characterizing chromatin accessibility, how accessibility is determined and remodelled in cells and the regulatory roles of accessibility in gene expression and development.
Recent studies have revealed the genome-wide reprogramming of gene expression upon exposure to stress, such as acute heat stress. Here, the authors review the molecular mechanisms that underlie stress-induced changes at promoters, enhancers and untranscribed loci.
Three-dimensional genome organization can shape gene expression by facilitating interactions between regulatory elements. The authors review the process of X-chromosome inactivation with a focus on chromatin organization and subnuclear localization of the active and inactive X chromosomes, as well as the potential roles of long non-coding RNAs.
The recent rise in obesity and its associated diseases has sparked intensive research into the transcriptional control of metabolic processes, collectively termed energy homeostasis. The authors review our current understanding of transcriptional and epigenetic regulators of energy homeostasis and crosstalk between pathways, and provide insights into emerging developments and challenges in this field.
In diploid organisms, expression from only one allele is frequently observed. This Review focuses on the widespread random monoallelic expression (RME) of autosomal genes, highlighting both the mitotically stable form observed in bulk analyses of cell populations and the recently discovered dynamic form identified through single-cell studies. The article also addresses the implications of different experimental criteria for calling monoallelic expression and potential biological roles in disease manifestations.
Synthetic biology approaches to characterize gene regulation have largely used transcription factor circuits in bacteria. However, the multilayered regulation of genes by chromatin in eukaryotes provides opportunities for more sophisticated control of gene expression. This Review describes diverse approaches for engineering eukaryotic chromatin states, the insights gained into physiological gene regulation principles, and the broad potential applications throughout biomedical research and industry.
Small and long non-coding RNAs have emerged as key regulators of gene expression through their direct and indirect actions on chromatin. This Review describes how RNAs form powerful surveillance systems that detect and silence inappropriate transcription events, and how such systems provide a memory of these events via self-reinforcing epigenetic loops.
This Review provides insights obtained from comparative transcriptomic studies of mammalian species. The dynamics of gene expression evolution in coding and non-coding genes, as well as the regulatory basis of transcriptome evolution and future research avenues, are discussed.
Gene-regulatory DNA elements control complex spatiotemporal patterns of gene expression, and alterations to these sequences are commonly associated with inter-individual phenotypic variation and human disease. This Review discusses our latest understanding of how different layers of information in these sequences control the binding of regulators and influence gene expression outcomes.
CCCTC-binding factor (CTCF) is a DNA-binding protein that has various, often seemingly contradictory, roles in gene regulation. This Review describes these disparate functions and how the context-dependent looping of DNA regions by CTCF is emerging as a potential unifying mechanism that underpins these diverse roles.
The rate and mechanisms of evolution of transcription factor binding show striking differences across diverse metazoan phyla. This Review highlights insights gained from sequence-based comparisons of genomes and ChIP–seq studies analysing the evolution of transcription factor binding, as well as their conceptual contribution to models of regulatory evolution and gene expression control.
This Review describes the diverse roles for histone-modifying and chromatin-remodelling enzymes in mammalian differentiation. These enzymes are involved in both maintaining pluripotency and specifying cell lineage commitment. Recent progress includes their functional characterization in mouse modelsin vivoand a new appreciation of their multifaceted molecular functions.
Our understanding of transcription is being improved through single-molecule and genome-wide approaches. Quantitative models are also required to provide insights into the underlying mechanisms of transcription, and the authors discuss how experimental results and models can be brought together.
Emerging evidence points towards RNA polymerase II promoter-proximal pausing as a widespread regulatory mechanism in higher eukaryotes. Here, the authors discuss the evidence for this from genome-wide studies and present potential functions of this regulatory mechanism.
How do transcription factors lead to defined developmental programs? The ways in which transcription factors act at enhancer elements and how enhancer activity is established during development are discussed in this Review, which brings together genetic and genomic evidence.
A suprisingly large proportion of mammalian genes are now known to be subject to random monoallelic expression. This Review discusses our latest understanding of the underlying mechanisms and of the implications for cellular functions and organismal evolution.
Organisms are exposed to various stresses, and responding rapidly and appropriately to these changes is crucial for survival. This Review describes how gene expression is regulated at many levels in response to stresses, including through signalling to chromatin or affecting transcriptional machinery.
Genome-scale methods are providing increasingly detailed views of nucleosome organization and chromatin structure. This is enhancing our understanding of how DNA-based reactions occur in the context of chromatin and how they are influenced by genome accessibility.
Methodological advances have provided new insights into mechanisms of enhancer function, including the importance of specific chromatin modifications at enhancers for the establishment of gene expression programmes. Cohesin and non-coding RNAs are also emerging as key players in enhancer function.
How are specific genomic regions targeted for transcriptional silencing and how is stable silencing maintained? The Polycomb and heterochromatin silencing systems have distinct roles and yet share some interesting features, such as the involvement of non-coding RNAs, histone modifications and dynamic protein complexes.
Genome-wide studies of protein–DNA interactions are helping to provide a more complete picture of the regulation of transcriptional programmes during plant development. Models of regulation have evolved from hierarchies of transcription factors to complex networks that involve these factors and chromatin-modifying proteins.
The multisubunit Mediator complex is a transcriptional co-activator that interacts directly with RNA polymerase II. The Mediator can also interact with and coordinate the action of numerous other co-activators and co-repressors, leading to distinct transcriptional outputs in response to different cellular signals.
Accumulating evidence suggests that core promoter recognition complexes have active roles in generating specific transcriptional programmes during development. Other new roles for components of these complexes have also been identified, such as maintaining gene expression states across cell divisions.
The rapid induction of specific sets of genes is required for cells to respond to external cues. Transcription of eukaryotic inducible genes is controlled at multiple steps, including activator recruitment and polymerase pausing, and is influenced by chromatin remodelling and signal transduction.
The classical model of gene activation by a unidirectional switch from co-repressor binding to co-activator binding is changing. This Review discusses emerging themes in the interplay among co-repressor complexes, enzymatic functions and chromatin modifications in controlling gene repression.
