Volume 31 Issue 1, January 2024

The concluding statement of Watson and Crick’s historic paper on the structure of DNA¹ enshrines a key tenet of molecular mechanistic cell biology: “… the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material”. Function — heredity in this case — is embedded in the redundant sequence information of the two strands of DNA. Although not always expressed as blatantly, the intimate dependence of cellular function on the mechanical level of macromolecules is inspirational. The devil is in the structural detail, and the painstaking quest for the correct details and their returns in the form of reliable knowledge knows no shortcuts.

Collaboration is key to modern science, with major advances using multiple complementary approaches and dependent on sophisticated infrastructure. Yet science is also highly personal, as each person carves out a reputation and career. How does this work out in reality, and how can communities be built to benefit science and scientists?

Here we investigate the role of epigenetics in the formation, transcription regulation, maintenance and termination of several non-canonical chromatin structures. Using two examples, we demonstrate how studying non-canonical structures may reveal underlying mechanisms with implications for disease and propose intriguing epigenetic avenues for further exploration.

Here, the authors discuss the various roles of the HUSH transcriptional silencing complex and its dysregulation in disease.

Here, using single molecule experiments, the authors show that the mechanical stability of cohesin encircling DNA is determined by its hinge domain that disengages at ~20 pN force, providing a framework for how cohesin counteracts spindle-generated tension during mitosis.

Many multipass membrane proteins are not fully inserted into the membrane when translation ends. Wu et al. now show that a membrane insertase called EMC can facilitate maturation of these proteins by post-translationally completing their insertion.

Here the authors show that TET dioxygenases, the erasers of DNA methylation, use a self-limiting mechanism via their LCD domain to ensure adaptable methylome status and protect the genome from excessive oxidative methylation.

Here the authors show that, when phosphorylated at Tyr34, THEMIS behaves as an allosteric activator to phosphatase SHP1, ensuring appropriate negative regulation of T cell antigen receptor signaling and thus assisting in T cell maturation and expansion.

Here, using structural and biochemical data, the authors revealed the assembly and working mechanism of helicase-primase D5 from Mpox virus.

The NLRC4 inflammasome, vital for immune defense, responds to infections and inflammation. Here the authors reveal the role of Bacillus thailandensis type III secretion system needle protein in activating NLRC4 complex through structural insights.

Here the authors delineate how pioneer factor Pax7 promotes chromatin relaxation, by initially mediating the deposition of activating marks and at times the removal of repressive chromatin modifications, subsequently enabling the recruitment of chromatin remodelers to displace nucleosomes and activate enhancers.

By probing the epigenome in differentiating DNA methylation-free murine ESCs, the authors uncover a subset of germline and neural enhancers sensitive to DNA methylation. Failure to decommission these elements leads to biased adoption of these fates over other lineages.

Here, using cryo-electron microscopy and functional assays in mouse oocytes and embryos, the authors delineate the composition of the subcortical maternal complex, showing that clinical variants associated with female reproductive diseases disrupt complex formation.

Here, the authors describe 3D hubs as regulatory subunits of gene expression in the three essential lineages of embryogenesis. They develop a computational model that can predict novel enhancers and they validate such enhancers in the context of specific lineages.

Here, using proteomics, next-generation sequencing, biochemistry and cryo-EM, the authors delineate the role of CedA as an unconventional transcription factor in Escherichia coli, which protects from different stressors, including antibiotics, by regulating the transcriptional landscape.

Using cryo-EM, Schmidt, Schulz, et al. solve the structure of the iron nitrogenase complex, which shows a unique architecture of alternative nitrogenases and suggests the G subunit to be involved in substrate channeling, stabilization of the cofactor and determining specificty among nitrogenase components.

Here, cryo-electron microscopy structures of sodium–glucose cotransporter 2, which is responsible for sugar reabsorption in the kidney and is a target for the treatment of type 2 diabetes, reveal a potential mechanism for cellular sugar uptake.

Here, the authors show that the complete set of the Atg8–E1–E2–E3 conjugation machinery forms an interaction web through multivalent weak interactions, which mediates membrane shaping observed during autophagosome formation.

The formation of the 2′–5′ lariat bond during branching is the critical first step in RNA splicing. A structure of a group II intron reveals a conserved base triple responsible for positioning the adenosine nucleophile to attack the 5′ splice site.

Here, the authors use a massively parallel reporter assay RNA polymerase II massively systematic transcript end readout, to quantify factors that influence transcriptional start site selection in the genome of Saccharomyces cerevisiae to reveal patterns of dependence on DNA sequence, RNA polymerase II activity and nucleoside triphosphate abundance.