News & Views in 2017

Chromatin remodelers are ATP-driven enzymes that can slide nucleosomes along DNA. Chen and colleagues present a tantalizing ∼4-Å view of the SWI/SNF ATPase motor bound to the nucleosome, which offers novel structural clues into the remodeling process.

The spatial organization of the genome profoundly influences how genes are regulated in normal development or dysregulated in disease. A new study of the murine HoxB locus illustrates how promoter interactions direct higher-order chromatin folding.

O-GlcNAc is a reversible post-translational modification that is added by O-GlcNAc transferase (OGT) and removed by O-GlcNAcase (OGA). OGA is emerging as a therapeutic target for multiple diseases, but its structure has been elusive until now.

One of the striking features of cells seen through a microscope is the heterogeneous organization of the nuclei. A combination of molecular methods and computational modeling has now been used to reconstruct accurate 3D structures of the genome inside single nuclei.

As cells undergo terminal differentiation, the composition of Polycomb-repressive complex 2 (PRC2) changes and the histone H3K27 methyltransferase Ezh2 is progressively replaced by its homolog Ezh1. By identifying an enzymatically inactive splice variant of Ezh1 that is sensitive to cellular stress, Bodega et al. now demonstrate that PRC2–Ezh1 has an essential role in establishing an altered gene expression program required for postmitotic muscle cells to adapt to environmental changes.

Chromatin-remodeling enzymes perform the formidable task of reorganizing the structure of a stable macromolecular assembly, the nucleosome. Recently published work demonstrates that the SNF2H chromatin remodeler distorts the histone octamer structure upon binding to the nucleosome, then taps into this induced plasticity to productively achieve nucleosome sliding.

The binding of foreign peptides to host major histocompatibility complex (MHC) forms the basis of adaptive immune recognition. The MHC and T cell receptors (TCRs) use diverse structural solutions to enhance peptide presentation and recognition, and two new reports provide insights into noncanonical modes of detection and binding.

Separases are crucial cell cycle proteases that control the metaphase-to-anaphase transition by cleaving chromosomal cohesin rings. Two new high-resolution structures of separase bound by its inhibitory chaperone securin illustrate intriguing regulatory mechanisms.

Unlike in animals in which gastrulation marks the onset of zygotic transcription and a transition from random to site-specific localization of replication origins, transcription and origin specification in Caenorhabditis elegans are in place before gastrulation. Nonetheless, origin-site redistribution takes place after gastrulation, and is coordinated with changes in the sites of active transcription.

Targeted deamination of cytosine bases in DNA by AID/APOBEC-family enzymes is critical for proper immune function, but it also poses risks to genomic integrity. New structures reported by Harris, Aihara and colleagues offer the first glimpses into the enzyme–DNA complex and reveal both expected and unexpected insights into the DNA-binding mode involved in targeting purposeful mutation.

Loss of function of the CFTR anion channel leads to cystic fibrosis, the most common inherited condition in humans of European origin. A recently reported structure for CFTR at 3.7-Å resolution reveals an unexpected 'lasso' domain and provides new insights into channel function in healthy individuals and in people with cystic fibrosis.

Determining the molecular mechanisms responsible for trinucleotide DNA repeat expansions is critical, as such expansions underlie many neuromuscular and neurodegenerative disorders. Mirkin and colleagues now propose that large-scale expansions of trinucleotide repeats can be generated by DNA-break-induced replication.

Little is known about the functions of long noncoding RNAs compared with the amount of accumulated knowledge concerning protein-mediated mechanisms. A report now proposes a novel RNA classification based on similar kinetics of RNA synthesis, processing and turnover, and the authors predict that RNAs within each class might share functional properties.

Warfarin has been the most widely prescribed anticoagulant for decades. It functions by inhibiting the membrane enzyme vitamin K epoxide reductase (VKOR), but the molecular details of this effect have remained elusive. Two new studies shed light on the warfarin-VKOR interaction. The work has implications for precision medicine and could guide drug discovery.

The site of HIV genome integration is likely a contributing factor in viral gene expression, but such context-specific effects are difficult to demonstrate at the population level. A new approach overcomes this obstacle by tracking individual, barcoded viruses to investigate the relationship between integration site location and the corresponding viral transcription, thereby providing insights essential for understanding HIV production, latency and reactivation.