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The role of promoters as potential insulator elements has been largely unexplored in mammals. Here the authors show that a single nucleotide variant in the α-globin locus forms a new promoter and acts as an orientation-dependent enhancer-blocking insulator element.

The chromatin remodeling complex ATRX can promote gene expression, for example by binding G-quadruplexes (G4s) to prevent their negative effect on expression. Here the authors use a single-cell approach to show that only a subset of erythroid cells isolated from patients with ATRX mutations have reduced chromatin accessibility and alpha globin expression, suggesting a stochastic process.

The relationship between regulatory elements, chromatin interactions and gene expression during development remains poorly understood. Here the authors present Tiled-C, a low-input 3C approach to study genome architecture at high resolution, and apply it to mouse erythroid differentiation in vivo, finding that enhancer-promoter interactions are formed gradually during differentiation, concomitant with progressive upregulation of gene activity.

Here the authors observe transcription dynamics in real-time throughout erythropoiesis by combining PP7 tagging of α-globin RNA transcripts and “on-microscope” cell staging. They show how the pattern of transcriptional bursting changes during differentiation, with variability in individual cells significantly reduced at the peak period of gene expression.

Globin loci harbor genes that are expressed embryonically and silenced postnatally. Here the authors show that zeta-globin silencing depends upon selective hypoacetylation of its TAD subdomain, which blocks its interaction with the alpha-globin super-enhancer, and zeta-globin can be reactivated by acetylation.

β-thalassemia is characterised by the presence of an excess of α-globin chains, which contribute to erythrocyte pathology. Here the authors use CRISP/Cas9 to reduce α-globin expression in hematopoietic precursors, and show effectiveness in xenograft assays in mice.

Mutations in the ADD domain of ATRX protein lead to severe mental retardation. Now the importance of this domain for targeting ATRX to heterochromatin is examined; ADD simultaneously recognizes unmethylated lysine 4 and trimethylated lysine 9 of histone H3, making it a combinatorial reader. This readout is enhanced by interaction with HP-1, forming a tripartite network that may bridge adjacent nucleosomes.

A new study addresses whether transcription of enhancers and the resulting enhancer RNAs (eRNAs) play a role in mediating long-range interactions between enhancers and promoters. Studying the immunoglobulin heavy chain (Igh) locus, the authors find that transcription of the enhancers per se is required to establish but not maintain these interactions, and this mechanism may apply to a subset of other enhancer–promoter interactions.

Hanssen et al. show that CTCF–cohesin binding sites at the α-globin gene cluster function as boundaries to restrict the interaction of enhancers with the flanking chromatin, thus preventing abnormal gene expression.

Douglas Higgs and colleagues functionally test the α-globin super-enhancer in mice by genetically deleting its constituent enhancers. They find that the individual regulatory elements seem to act independently and in an additive way with respect to hematological phenotype, gene expression, and chromatin structure and conformation.

In the cell, genomic DNA is transcribed into various types of RNA. But not all RNAs are translated into proteins. Does this give protein-coding RNAs greater credibility in terms of function? Views differ.

In this Viewpoint, five experts discuss our biological understanding of super-enhancers, how we can responsibly study their functions, and their opinions on whether names for enhancer clusters are an informative reflection of their functional properties.

Douglas Higgs and colleagues report a high-throughput approach, called Capture-C, to analyze interactions between cis regulatory elements. Using Capture-C, the authors interrogated hundreds of specific interactions at high resolution in a single experiment.

In this Review, Oudelaar and Higgs discuss the relationship between genome structure and gene regulation, with a focus on whether genome organization has an instructive role or largely reflects the activity of regulatory elements.

Many proteins that canonically function in the cytosol can also localize to the nucleus. The authors propose that a distinct group of such proteins (which they name STRaNDs) engage in a particular mode of signal transduction, whereby in response to extracellular cues, the cytosolic protein transits to the nucleus and regulates gene expression without direct DNA binding.