Like the gears of a sophisticated clockwork, chromatin regulation consists of diverse interconnected pathways that control outputs such as gene transcriptional regulation. In this issue of Nature Genetics, Morgan and Shilatifard discuss recent progress in understanding the catalytic and non-catalytic functions of histone-modifying enzymes in transcriptional regulation and other DNA-templated processes. On this cover, the chromatin-regulatory network is depicted as a system of gears that represent nucleosomes, connected by DNA, with gauges representing functional outputs such as gene expression.

See Morgan & Shilatifard

The genome undergoes three-dimensional organization and folds into topologically associating domains (TADs). However, the nature and folding of TADs in single cells have remained obscure. The use of optical super-resolution microscopy has revealed that averaged TADs identified through Hi-C (represented here inside the prism) emerge from a wide variety of individual TAD structures that have diverse shapes and can be subdivided into heterogeneous chromatin nanodomains (seen here as the structures emerging from the diffracted light ray). Furthermore, quantitative microscopy enables dissection of the roles of CTCF, cohesin and nucleosome interactions in the regulation of TAD and chromatin nanodomain architecture, illustrating the power of imaging to reveal single-cell genome organization.

See Szabo et al.

Ankole cattle are found in Uganda, Rwanda, Burundi, Tanzania and the Democratic Republic of Congo. Highly social and renowned for their calm demeanor, these large, graceful animals bearing improbably massive horns are also prized for their hardiness: they can subsist on poor-quality vegetation, endure long droughts and walk hundreds of miles to reach new water and grazing resources.

See Kim et al.

In temperate regions of Europe, early-maturing and cold-tolerant flint landraces were key to maize cultivation. Delineating the core and dispensable genome of four European flint and two North American dent maize lines unveils similarities and differences between the two germplasm groups. Pronounced variation in haplotypes, heterochromatic knobs and orthologous long-terminal-repeat retrotransposons reveals the exceptional dynamics of the maize genome.

See Haberer et al.

As reported by Gagliardi et al., human papillomavirus (HPV) is found integrated within the genome in most cervical tumors, and often is associated with marked epigenetic and transcriptional activation of the surrounding chromatin. The circular arrangement shows the profile of histone modifications observed with ChIP–seq across the HPV-integration events in the cluster with the highest increase in enrichment, as shown in Fig. 5f. It is composed of data sampled from two randomly paired individuals, with tracks facing inward and outward for each individual. Individuals are paired randomly, and track colors correspond to five histone marks with epigenetic enrichment.

See Gagliardi et al.

In this issue, Enache, Rendo et al. show that the expression of guide-free Cas9 in human cell lines can lead to DNA damage, thus resulting in p53 activation. This can sometimes result in the emergence or expansion of p53-inactivating mutations. On the cover, p53 is depicted as the ‘watchdog’ of the genome garden. It is trying to bark away Cas9 ‘bunnies’ and prevent them from cutting the DNA. The watchdog and bunnies are based on the crystal structures of p53 and Cas9, respectively.

See Enache et al.

Lions (MLL2/COMPASS) keep zebras (PRC2) away, allowing the boat (RNA polymerase II) to travel down the river (DNA). When lions are not around (MLL2 knockout), zebras and crocodiles (DNA methyltransferases) block the boat. Without any animals, the boat is free to navigate.

See See Douillet et al.

This double-helix-shaped cyclone of sweetener packets depicts the detrimental effect of increased sorbitol levels on peripheral nerves, caused by biallelic mutations in the sorbitol dehydrogenase (SORD) gene.

See Cortese et al.

The cover image depicts the creation of a 3D chromosomal landscape in a leukemia cell, described in Kloetgen et al. This study identifies a TAD fusion and separation events responsible for activation of oncogenes and silencing of tumor suppressors.

See Kloetgen et al.

Circos plots found in the eyes of peacock feathers represent the rearranged state of cancer whole genomes. The types of genomic lesions and the extent of chromosomal abnormalities were characterized by the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium established by the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). These tumor sequencing data will serve as a rich resource for the cancer genomics community.

See Cortés-Ciriano et al. Zapatka et al. Yuan et al. Akdemir et al. Rodriguez-Martin et al.

The cover image depicts an analogy often used by teachers of molecular genetics courses when describing slipped-strand DNA: DNA is like a zipper made of two strands, Watson and Crick. Usually, the zippers’ teeth pair perfectly, but in repetitive DNAs, the zipper can get jammed by misaligned pairing of the teeth, thus producing slipped-DNA structures. Slipped DNAs formed by disease-causing CAG/CTG-repeating DNAs can be incorrectly repaired and can consequently yield repeat mutations, which are known to cause at least 17 human neurodegenerative and neuromuscular diseases, such as Huntington’s disease (HD). Ongoing repeat expansions arise in affected tissues and contribute to disease onset, progression and severity. Arresting or reversing somatic repeat expansions should arrest or reverse disease onset, progression and severity. In HD model mice, a small molecule that targets the expansion process by specifically binding slipped-CAG repeats can induce contractions of the expanded repeat in the striatum, a vulnerable brain region in people with HD. Essentially, this treatment can reverse the disease-causing repeat expansions.

See Nakamori et al.

Image of the hooded Indian cobra, showing a pair of characteristic dark lateral spots on the throat (right). The image on the left is of the dorsal side of the Indian cobra, with the hood showing two characteristic false eyespots connected by a curved line. This medically important, highly venomous snake is found throughout the Indian sub-continent. The near-chromosomal genome assembly identified key venom toxins that will enable rapid development of safe and effective synthetic antivenom. The photos are of an adult male Indian cobra taken at the Madras crocodile bank, Chennai, India (image courtesy of Romulus Whitaker and Ajay Karthik).

See Suryamohan et al.