Volume 55 Issue 2, February 2023

Endometriosis affects around 10% of individuals born with a uterus, yet we know remarkably little about its underlying biology. Our single-cell transcriptional profiling of endometrial-type epithelial and stromal cells is shedding light on the cells and processes that contribute to endometriosis, which opens up new avenues for diagnostics and therapeutics.

Current methods of chromatin analysis focus mainly on the most abundant cell types in a sample. We present a workflow that combines enrichment of rare cell types with high-resolution mapping of histone modifications, which enables us to study chromatin dynamics in rare stem and progenitor cell populations.

A high-throughput reporter gene assay for use in living tissues has been developed. The assay allows investigators to quantify, in parallel, the activities of reporter genes in each of the cell types that constitute a tissue.

Using a series of mouse mutants, we found that the Sox2 promoter does not require CTCF–cohesin loops to interact with distal enhancers. Surprisingly, mice with varying numbers of CTCF motifs in different positions showed that some distal enhancers can bypass boundaries that are created by CTCF–cohesin loops to ensure robust Sox2 expression.

Using laser-capture microdissection and whole-genome sequencing of individual crypts, we characterized the landscape of somatic mutations in human small intestinal epithelium. Mutational signatures of APOBEC mutagenesis were found frequently and are probably due to the activity of APOBEC1, which is expressed at high levels in the small intestine.

This Perspective article discusses Singapore’s efforts to implement a National Precision Medicine Strategy through the integration of genomic, clinical and lifestyle data of up to one million Singaporean individuals.

Genome-wide analyses in BioBank Japan and populations of European ancestry identify new risk loci for atrial fibrillation. A polygenic risk score constructed from the cross-ancestry meta-analysis is associated with increased risk of long-term cardiovascular mortality.

Genome-wide analyses identify 27 loci associated with attention-deficit hyperactivity disorder and provide insights into its genetic architecture in relation to other psychiatric disorders and cognitive traits.

This Brain Somatic Mosaicism Network analysis of 283 cases of malformations of cortical development identifies 69 candidate and known genes in 76 patients. Single-nucleus RNA sequencing and mouse modeling implicate radial glia and daughter excitatory neurons.

DeepNeo identifies major histocompatibility complex (MHC) I or MHC II neoepitopes that are immunogenically compatible with the T cell repertoire. It can predict neoepitopes most likely to be depleted through spontaneous immunity or through immune checkpoint blockade from untreated and immunotherapy-treated tumor datasets.

Notch1 mutations have opposing effects on clonal growth in normal and tumor cells of the mouse esophagus. In a mouse model of squamous esophageal tumorigenesis, Notch1 blockade reduced premalignant tumor growth, suggesting that it might be an effective prevention strategy for the disease.

Whole-genome sequencing of healthy human epithelial crypts from the small intestines of 39 individuals highlights APOBEC enzymes as a common contributor to the overall mutational burden in this tissue.

A single-cell transcriptomic analysis of endometriosis, endometriomas, eutopic endometrial samples and uninvolved ovary tissues highlights cell populations characteristic of these tissue types. Transcriptional and cellular heterogeneity across tissues suggests novel therapeutic targets and biomarkers for this disease.

In aging mouse livers, 40% of elongating RNA polymerases are stalled, biasing transcriptional output dependent on gene length. This transcriptional stress appears to be caused by endogenous DNA damage.

Genetic manipulation of the Sox2 locus in mice shows that gene activation by distal enhancers does not require CTCF-mediated loops and can occur across ectopic CTCF-mediated boundaries. The ability to bypass CTCF boundaries varies with their insulation strength and the tissue-specific enhancers responsible for activation.

A multi-ancestry transcriptome-wide association study using an optimal linear combination of association statistics provides insights into tobacco use biology and suggests opportunities for drug repurposing.

A high-quality Ixodes scapularis genome contributes to improved annotations, expansion of gene families, development of proteome catalogs and the deciphering of genetic variation in wild ticks.

De novo genome assembly and analyses of 12 maize FILs provide insights into genomic and phenotypic differentiation of various heterotic groups and the molecular basis of heterosis in maize.

Re-analysis of published RNA-sequencing samples finds that unannotated splicing events predict, with high sensitivity, the activation of exon skipping and cryptic splicing by splice-site variants.

Sort-assisted single-cell chromatin immunocleavage (sortChIC) combines single-cell histone modification profiling with fluorescence-activated cell sorting (FACS), enabling the study of rare cell populations. H3K4me1/H3K4me3, H3K9me3 and H3K27me3 profiling of blood suggest a model of lineage-shared repressive and cell type-specific active chromatin.

A single-cell massively parallel reporter assay is used to compare cis-regulatory sequence activities in cell line models and mouse retinal tissue ex vivo, identifying cell state- and cell-type-specific effects of sequence variation.