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DNA methylation is associated with breast cancer risk. Here the authors measure DNA methylation in the blood of individuals from 25 Australian families with multiple cases of breast cancer but not known mutations associated with breast cancer risk to identify possible heritable methylation markers.

Massively parallel reporter assay in primary human CD4⁺ T cells and bulk and single-cell CRISPR-interference screens identify candidate causal variants linked to autoimmune disease risk that modulate T cell gene expression and proliferation.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.

Epigenetic aberrations can affect gene regulation and impact diseases, but understanding these regulatory connections remains challenging. Here, the authors present MethNet, a pipeline to integrate DNA methylation and gene expression profiles across multiple cancers to uncover distal cis-regulatory element hubs and their functional impact.

Long-read chromatin assay reveals (1) a novel class of accessible chromatin regions, (2) accessibility within individual LTR retrotransposons and (3) the relationship between diffuse accessibility, gene body methylation and hAT transposon insertion.

Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.

Mammalian gene silencing is associated with both histone and DNA methylation. The PRMT5 arginine histone methyltransferase is now found to affect DNA methylation at the γ-globin locus in mice. This is mediated by an effect on recruitment of the DNA methyltransferase DNMT3A, but through interaction with the product of PRMT5 activity. This suggests that DNMT3A reads the histone methylation, coupling it to nearby DNA methylation.

Here, the authors perform large trans-ancestry fine-mapping analyses identifying large numbers of association signals and putative target genes for colorectal cancer risk, advancing our understanding of the genetic and biological basis of this cancer.

Here, the authors unveiled a ‘super-silencer’ and its mechanisms of action. They revealed that a combined treatment of an enhancer of zeste homolog 2 inhibitor and a repressor element 1-silencing transcription factor inhibitor can disrupt super-silencers, potentially leading to cancer ablation.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Systemic sclerosis (SSc) is a heterogeneous chronic autoimmune disease that affects the connective tissue. Here, López-Isac et al. identify 13 new risk loci for SSc as well as loci specific for limited cutaneous and diffuse SSc and, defining credible sets and performing functional annotation, highlight key pathways and cell types for SSc.

The number of germline stem/progenitor cells in C. elegansdeclines with age. Here the authors show this cell loss is mediated by the transcription factor DAF-16/FOXO acting in specific somatic gonad cells, demonstrating that stem cell aging can be anatomically uncoupled from organismal aging.

Many transcription factors bind to regulatory DNA elements that are distant from gene promoters. These distal binding sites are thought to regulate transcription through long-range chromatin interactions, but, until now, the impact of chromatin interactions on transcription regulation has not been investigated in a genome-wide manner. A new strategy — chromatin interaction analysis by paired-end tag sequencing — is now described for the de novo detection of global chromatin interactions.

Oestrogen negative breast cancer is associated with a poor prognosis. In this study, the authors perform a meta-analysis of 11 breast cancer genome-wide association studies and identify four new loci associated with oestrogen negative breast cancer risk. These findings may aid in stratifying patients in the clinic.

Prostate cancer is a common cause of male cancer-related deaths. Complete sequencing of prostate cancer genomes now reveals previously unknown balanced rearrangements. Single-nucleotide resolution afforded by sequencing indicates that complex rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.

This study demonstrated that different types of HC-Pros from potyviruses exhibit varying capacities to inhibit HEN1. This results in distinct levels of autophagic AGO1 degradation, which in turn leads to differences in RNA silencing suppression efficiency.

Prior evidence suggested mesenchymal stromal cells (MSCs) required for skeletal formation, maintenance, and repair arise postnatally. Here, the authors show that Hoxa11 lineage-marked cells give rise to all skeletal lineages from embryogenesis through adulthood and are upstream progenitors of LepR- and Osx-lineage MSCs

Multimodal DNA methylation and transcriptome profiling of single glioma cells links tumor cell transcriptional states to epigenetics via interaction with PRC2 and shows that these states are heritable and important for tumor plasticity.

SARS-CoV-2 vaccination has shown reduced efficacy in patients with haematological malignancies. Here, the authors show that a third vaccine is able to enhance SARS-CoV-2 antibody responses in most cases in a cohort of 381 patients with haematological malignancies.

The SiO₂ contents of erupted volcanic melts are correlated with persistent seismic signals that accompany eruptions—volcanic tremor—and may represent an eruption monitoring tool, according to a study of volcanic ash glasses from Cumbre Vieja volcano.

The next step after sequencing a genome is to figure out how the cell actually uses it as an instruction manual. A large international consortium has examined 1% of the genome for what part is transcribed, where proteins are bound, what the chromatin structure looks like, and how the sequence compares to that of other organisms.

Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.

The expression of CD4, a critical co-receptor providing T cell help in adaptive immunity, is finely tuned during development. Here the authors show that two enhancer elements, E4p and the newly-defined E4m, coordinate the expression and heritable demethylation of Cd4 in thymocytes but are dispensable for its sustained expression in peripheral T cells.

Here the authors unveil the essential role of MCL-1 for adult hair follicle regeneration and inhibition of proliferation stress-induced apoptosis in mice. They also identify a P53/MCL-1/BAK axis balancing proliferation and death of activated hair follicle stem cells to ensure proper hair growth.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

Through the use of a novel three-dimensional imaging technique, used in conjunction with a multicolour reporter that allows lineage tracing and cell tracking of entire mammary ducts in vivo, bipotent stem cells are shown to have a central role in both puberty and long-term maintenance; in addition, long-lived luminal progenitor cells with a prominent role in ductal expansion are identified.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

In yeast cells, short telomeres are preferentially elongated by the telomerase complex in a process that requires Tel1. Now low levels of telomerase inhibitory protein Rif2 and the absence of Mec1 are shown to mark short telomeres for Tel1 binding and elongation rather than double-strand break repair.

The original Cancer Cell Line Encyclopedia (CCLE) is expanded with deeper characterization of over 1,000 cell lines, including genomic, transcriptomic, and proteomic data, and integration with drug-sensitivity and gene-dependency data.

In individuals who have achieved natural control of HIV-1 without drug treatment, intact proviral sequences are integrated into genomic regions that are not permissive to active viral transcription, indicating deep latency of the virus.

In multiple myeloma, a 4;14 translocation induces overexpression of histone methyltransferase NSD2, resulting in expansion of H3K36me2 and shrinkage of H3K27me3 domains. Here the authors find that CTCF, H3K27ac and gene expression changes cluster within a subset of insulated domains implicating 3D chromosome organization as a key factor in the NSD2-mediated phenotype.

Puberty is an important developmental period marked by hormonal, metabolic and immunological changes. Here the authors report gene expression changes in immune cells associated with age and puberty, and that may be relevant for sex differences in susceptibility to asthma, in a longitudinal cohort of 251 children with asthma.

Mechanisms underlying gene repression and silencers remain poorly understood. Here the authors investigate the role of H3K27me3-rich regions in the genome, as defined from clusters of H3K27me3 peaks, in regulating gene expression via looping.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Paul Pharoah and colleagues report the results of a large genome-wide association study of ovarian cancer. They identify new susceptibility loci for different epithelial ovarian cancer histotypes and use integrated analyses of genes and regulatory features at each locus to predict candidate susceptibility genes, including OBFC1.

There is lack of therapies targeting the PAX3-FOXO1 fusion oncogene in fusion-positive rhabdomyosarcoma (FP-RMS). Here, the authors identify and characterise an inhibitor with highest inhibition of histone lysine demethylase 3B that suppresses PAX3-FOXO1 activity in FP-RMS.

Environmental influences during prenatal development may have implications for health and disease later in life. Here, Czamara et al. assess DNA methylation in cord blood from new-born under various models including environmental and genetic effects individually and their additive or interaction effects.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.