Reviews & Analysis

The impact of endogenous retrovirus silencing during mammalian development is poorly understood. A new study shows that their abnormal reactivation in pluripotent cells dismantles key gene regulatory networks by perturbing transcriptional condensates linked to super-enhancer function.

A machine-learning model produces summarized sequence representations of genomic regulatory activity, and provides a functional view of regulatory DNA variation in the human genome, with the aim of better understanding the role of sequence variation in health and disease.

The boundaries of chromatin domains have an important role in genome organization and regulation. A comprehensive genetic dissection of a domain boundary in vivo provides insights into how boundary elements function and cooperate to mediate insulation between chromatin domains.

A large-scale collaborative effort now provides a comprehensive annotation of functional non-coding elements in the zebrafish genome. This work serves as an essential foundation for future studies to understand how gene regulatory circuits control embryonic development.

The use of association studies to identify candidate genes for complex biological traits in plants has been challenging due to a reliance on single reference genomes, leading to missing heritability. Graphical pangenomes and the identification of causal variants help overcome this and provide an important advance for crop breeding.

A new study employs CRISPR–Cas9-based base editing for simultaneous mutagenesis of all copies of histone H3 genes in mammals, highlighting the functional importance of H3K27me3 for Polycomb-mediated gene silencing and the dispensability of H3K27ac in transcriptional activation.

A new study highlights a strategy to link SNPs implicated in human complex traits and diseases with probable causal genes. This method prioritizes genes for functional characterization and helps address questions about the architecture of human phenotypes.

A new study demonstrates that the disordered N-terminal domain of DNMT3A1 binds PRC1-catalyzed H2AK119ub, targeting DNA methylation to bivalent promoters in mouse brain cortical cells. Methylation around bivalent genes is critical for mouse postnatal development, and could be equally important in other cell types and in disease.

Defining the most appropriate phenotypes in genome-wide association studies of COVID-19 is challenging, and two new publications demonstrate how case-control definitions critically determine outcomes and downstream clinical utility of findings.

Chromosomes are shaped by an interplay between loop extrusion and compartmentalization. Two new studies demonstrate that bromodomain and extraterminal domain (BET) proteins contribute to both processes, with BRD4 facilitating one process and surprisingly inhibiting the other.

The largest genetic study of educational attainment (EA) so far combines gene mapping and family analyses to show that genetic associations with EA and its health benefits may be mostly indirect. As such, future genetic studies of human social and behavioral traits must include diversity in population, demographic and environmental contexts.

A new study demonstrates that profiles of nascent RNA accurately predict genomic patterns of histone modifications and chromatin state. Consistent with that, active histone marks are revealed to reflect transcription activity, rather than preceding or directing gene output.

The gap between heritability estimates from twin studies and those from genotyping array data has puzzled researchers for over a decade. New research suggests that much of the ‘missing’ heritability is due to rare variants that can only be captured by whole-genome sequencing (WGS) data.

Similar to CTCF, MAZ insulates repressed posterior Hoxa genes from the spreading of anterior active regulatory cues during motoneuron differentiation. This discovery provides new perspectives to understand chromatin organization and insulation.

The function of transposable elements present in mammalian genomes remains an enigma. In this issue, Bodega, Abrignani and colleagues show that LINE1-containing transcripts are key regulators of T cell effector function and exhaustion.

Complex disease definitions often represent descriptive umbrella terms of symptoms rather than mechanistic entities. A new study shows how network-based approaches can help identify the mechanisms that link genes, cells, tissues and organs in cardiovascular diseases.

Although clear genetic connections to ALS were first established three decades ago, there has been negligible progress in the development of disease-modifying treatments for this disease. Despite tremendous unmet need, industry has often been largely baffled by a disease seemingly designed to thwart current effective drug development approaches. In the largest genetic study of ALS to date, van Rheenen and colleagues use sophisticated analyses to gain novel insights into its pathogenesis.

The human endometrium exhibits complex signaling cascades mediated by spatial–temporal cellular interactions. Understanding the normal endometrial microenvironment is the first step towards understanding diseases of endometrial dysfunction.

Oncogene amplification is a major driver of tumorigenesis; yet, the mechanisms generating amplification are only partially understood. New research reports on the identification of a new focal amplification pattern termed ‘seismic amplification’ that is hypothesized to originate from recombination between extrachromosomal DNA circles.

How somatic and germline mutations interact in cancer remains largely unexplored. A study of 17,152 patients with cancer suggests that the relative contribution of pathogenic germline mutations is governed by lineage and penetrance.