Focus |

Genomes and Epigenomes

Rebecca Furlong: human genetics and evolutionary genomics. 

Anne Mirabella: genome instability, DNA repair and replication.

Carolina Perdigoto: chromatin, epigenetics and transcription.

Katie Ridd: cancer genomics and cancer epigenomics.

Welcome to the Nature Communications Editors’ Highlights webpage on genomes and epigenomes. Each month our editors select a small number of Articles recently published in Nature Communications that they believe are particularly interesting or important.

The aim is to provide a snapshot of some of the most exciting work published in the area of genomes and epigenomes at Nature Communications.

Make sure to check the Editors' Highlights page each month for new featured articles.

Rebecca Furlong

The prevalence of cardiometabolic diseases (CMDs) is increasing rapidly across Africa. Here, the authors investigate autozygosity in CMD-associated traits in over 10,000 sub-Saharan African individuals, showing these traits are influenced by sex-specific inbreeding depression and environmental interactions.

Article | Open Access | | Nature Communications

Mendelian randomization is a useful tool to infer causal relationships between traits, but can be confounded by the presence of pleiotropy. Here, the authors have developed MR-link, a Mendelian randomization method which accounts for unobserved pleiotropy and linkage disequilibrium between instrumental variables.

Article | Open Access | | Nature Communications

How Indigenous populations in the southern tip of South America have changed over time has been unclear. Here the authors generate genome-wide data for 20 ancient individuals and examine how past migrations and admixture events correlate to geography and shifts in the archaeological record.

Article | Open Access | | Nature Communications

Structural variants (SVs) contribute to the genetic architecture of many brain-related disorders. Here, the authors integrate SV calls from genome sequencing (n = 755) with RNA-seq data (n = 629) from post-mortem dorsal lateral prefrontal cortex to annotate the gene regulatory effects of SVs in the human brain and their potential to contribute to disease.

Article | Open Access | | Nature Communications

Horseshoe crabs have been morphologically stable across evolutionary time. Here, the authors generate a chromosome-level assembly for the mangrove horseshoe crab, with implications for innate immunity, and challenging assumptions about the role of genome duplication in adaptive radiation.

Article | Open Access | | Nature Communications

European populations underwent strong genetic changes during the Neolithic. Here, Furtwängler et al. provide ancient nuclear and mitochondrial genomic data from the region of Switzerland during the end of the Neolithic and the Early Bronze Age that reveal a complex genetic turnover during the arrival of steppe ancestry.

Article | Open Access | | Nature Communications

Membranous nephropathy (MN) is a rare autoimmune disease of podocyte-directed antibodies, such as anti-phospholipase A2 receptor. Here, the authors report a genome-wide association study for MN and identify two previously unreported loci encompassing the NFKB1 and IRF4 genes and additional ancestry-specific effects.

Article | Open Access | | Nature Communications

Vitamin D is a precursor of the steroid hormone 1,25-dihydroxyvitamin D3, and its deficiency is associated with many adverse health outcomes. Here, Revez et al. perform a genome-wide association study for circulating 25-hydroxyvitamin D in 417,580 individuals and test for potential causal relationships with other traits using Mendelian randomization.

Article | Open Access | | Nature Communications

Anne Mirabella

The fork protection complex (FPC), including the proteins TIMELESS and TIPIN, stabilizes the replisome to ensure unperturbed fork progression during DNA replication. Here the authors reveal that that SDE2, a PCNA-associated protein, plays an important role in maintaining active replication and protecting stalled forks by regulating the replication fork protection complex (FPC).

Article | Open Access | | Nature Communications

The origin recognition complex (ORC) is essential for loading the Mcm2–7 replicative helicase onto DNA during DNA replication initiation. Here, the authors describe several cryo-electron microscopy structures of Drosophila ORC bound to DNA and its cofactor Cdc6 and also report an in vitro reconstitution system for Drosophila Mcm2–7 loading, revealing unexpected features of ORC’s DNA binding and remodeling mechanism during Mcm2–7 loading.

Article | Open Access | | Nature Communications

DNA damage sensors DDB2 and XPC are fundamental factors to initiate global genome nucleotide excision repair and protect DNA from mutagenesis. Here the authors reveal that ubiquitin and TFIIH-stimulated DDB2 dissociation promotes DNA damage handover to XPC in nucleotide excision repair.

Article | Open Access | | Nature Communications

While R-loops can alter cell homeostasis, it is unclear what determines their toxicity. Here, the authors, by using Top1 knockdown as a tool to enhance the formation of R-loops at certain genomic sites, reveal and characterize a proportion of R-loops that are more toxic to the cell by causing DNA damage.

Article | Open Access | | Nature Communications

In mammalian cells, during transcription and replication, RNA:DNA hybrid structures known as R-loops can arise, posing as obstacles to replication fork progression. Here the authors reveal that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication associated DNA damage in cancer cells.

Article | Open Access | | Nature Communications

In order to avoid transcription-replication conflicts (TRCs) on shared DNA templates, cell must maintain strict spatiotemporal co-ordination of transcription with replication. Here the authors uncover a role for BRD4 in preventing TRCs and DNA damage checkpoint signaling in oncogenic cells.

Article | Open Access | | Nature Communications

Carolina Perdigoto

The boundaries of topologically associating domains (TADs) arise from the ability of the CTCF protein to stop extrusion of chromatin loops by cohesin. Here the authors find that CTCF positions cohesin through its N-terminus but does not control its overall binding dynamics on chromatin, and show how the orientation of CTCF binding sites translates into genome folding patterns.

Article | Open Access | | Nature Communications

The conserved SAM motif of Polycomb Repressive Complex 1 subunit Ph has been shown to play an important role in chromatin organization. Here, the authors study the effect of Ph SAM on chromatin in vitro, showing that it induces the formation of concentrated, phase-separated condensates, which enhance the ubiquitin ligase activity of PRC1.

Article | Open Access | | Nature Communications

Here, the authors perform ATAC-seq on four distinct cell populations from three different regions of the human brain, finding that chromatin accessibility varies greatly by cell type and less by brain region. This study reveals differences in biological function and gene regulation, as well as overlap of genetic variants associated with schizophrenia and other neuropsychiatric traits.

Article | Open Access | | Nature Communications

Bulk approaches fail to capture the cell-to-cell heterogeneity of chromatin landscapes, while single-cell approaches provide low coverage datasets. Here, the authors present ChromSCape, a user-friendly interactive application that processes single-cell epigenomic data to assist the biological interpretation of chromatin landscapes within cell populations, as demonstrated in the context of cancer.

Article | Open Access | | Nature Communications

The paternal genome in mice undergoes widespread DNA methylation loss post-fertilization. Here, the authors apply allele-specific analysis of WGBS data to show that a number of genomic regions are simultaneously de novo methylated on the paternal genome dependent on maternal DNMT3A activity, which induces transcriptional silencing of this allele in the early embryo.

Article | Open Access | | Nature Communications

Human Microrchidia 4 (MORC4) ATPase has been implicated in acute and chronic pancreatitis, inflammatory disorders and cancer. Here the authors describe the structure–function relationship of MORC4 and define the molecular mechanism for MORC4 activation.

Article | Open Access | | Nature Communications

Chromatin state underlies cellular function, and transcription factor binding patterns along with epigenetic marks define chromatin state. Here the authors show that the histone chaperone ANP32E functions through regulation of H2A.Z to restrict genome-wide chromatin accessibility and to inhibit gene transcriptional activation.

Article | Open Access | | Nature Communications

Nucleosome turnover concomitant with incorporation of the histone variant H3.3 is a hallmark of regulatory regions in the animal genome. Here, the authors demonstrate that fast histone turnover and H3.3 incorporation defines a dynamic heterochromatin state in pluripotent stem cells.

Article | Open Access | | Nature Communications

Neuronal differentiation requires rearrangement of the transcriptional and chromatin landscapes of neural cells. Here, the authors study in-vitro neuronal differentiation of murine embryonic stem cells (ESCs) to show that this process is modulated by DOT1L activity, which regulates H3K79me2 accumulation, and preserves accessibility of SOX2-bound enhancers.

Article | Open Access | | Nature Communications

Katie Ridd

Cancers deficient in homologous recombination can benefit from treatment with poly ADP-ribose polymerase (PARP) inhibitors. Here, the authors generated a classifier that can predict homologous recombination deficiency from genomic data and suggest several cancer types that may benefit from PARP inhibitor treatment.

Article | Open Access | | Nature Communications

The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. Here, the authors use deep genomic sequencing and histopathological information to trace tumor evolution both within the prostate and during metastasis in ten men.

Article | Open Access | | Nature Communications

There are currently only a few biomarkers to predict the response of muscle invasive bladder cancer to therapy. Here, the authors analyse 300 tumors using exome and RNA sequencing and find that tumors with a high degree of genomic instability and a non-basal/squamous gene expression subtype are most likely to respond to treatment.

Article | Open Access | | Nature Communications

Pancreatic ductal adenocarcinoma may be initiated by acinar metaplasia, but the molecular and cellular insights during this transition are unclear. Here the authors show, using single cell RNA-sequencing analyses, that mouse metaplastic acinar cells can be clustered into six cell types or states that are heterogeneous and have unique transcription programs.

Article | Open Access | | Nature Communications

Schizophrenia has been associated with increased risk of breast cancer, yet the risk of schizophrenia following breast cancer is unclear. Here, the authors show a bidirectional association between breast cancer and schizophrenia in Sweden and a shared genetic contribution to both diseases.

Article | Open Access | | Nature Communications

Mongolia has the highest incidence of—and mortality from—hepatocellular carcinoma (HCC) in the world. Here, the authors examine the genomic and transcriptomic landscape of Mongolian HCC, uncover novel driver mutations, and suggest distinct disease etiologies.

Article | Open Access | | Nature Communications

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Article | Open Access | | Nature Communications

Here the authors show that stronger immune selection and immune editing in females and younger patients lead to the accumulation of poorly presented driver mutations in tumors. These results may explain why young and female patients are characterized by lower response rates to immune checkpoint blockade therapies.

Article | Open Access | | Nature Communications