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Transitional liver progenitor cells, which derive from biliary epithelial cells, differentiate into hepatocytes after serious liver damage. The cover illustrates this regenerative process, as new hepatocytes (green leaves) are formed and emerge via the biliary ducts.
David Allis (1951–2023) was a leading figure in the field of chromatin biology. He inspired many generations of scientists both through his work and his own personal example as a mentor and colleague. His influential ‘histone code’ theory remains an important guiding principle to study and understand gene regulation.
Specific chromatin features, especially histone H3 lysine 27 acetylation, are widely used to identify active enhancers, yet current methods are imprecise. New work suggests that histone H2B N terminus multisite lysine acetylation (H2BNTac) is a notable signature of active enhancers and could substantially improve enhancer prediction.
Quantifying whether different populations share similar effect sizes of common causal variants is vital to understand the genetic basis of disease and build better prediction models. A new study proposes a method leveraging admixture to estimate the correlation of causal genetic variants and finds they are largely similar across ancestry backgrounds.
A new study deciphers the origin and evolution of childhood neuroblastoma using genome sequencing data, mathematical models and statistical inference, showing how neuroblastoma evolution is an accurate predictor of outcome.
Telomere length is an important determinant of cellular aging and disease risk, but the genetics of telomere length control in humans is unclear. A genome-wide CRISPR screen has now identified a central role for thymidine nucleotide metabolism in the regulation of telomere length, which has implications for the diagnosis and treatment of disease.
A study uses single-cell RNA sequencing to profile human papillomavirus (HPV)-positive and -negative oropharyngeal squamous cell carcinoma, revealing considerable diversity within and between tumors. Within HPV-positive tumors, subsets of malignant cells are found with undetectable HPV expression and decreased HPV-related phenotypes, which may influence prognosis and response to therapy.
How histone modifications are reprogrammed through germline development in plants is poorly understood. We found that H3K27me3 and H3K4me3 are extensively reprogrammed throughout the development of Arabidopsis male gametophyte. This reprogramming leads to widespread chromatin bivalency and selective removal of H3K27me3 marks from key developmental regulators in sperm.
Transposable elements (TEs) are transcriptionally activated in cancer and can generate chimeric TE–gene transcripts that are tumor specific. Our pan-cancer study reveals that these transcripts are a source of tumor-specific antigens that are shared across tumor types, bind to HLA and are presented on the extracellular surface of cancer cells appended to membrane-bound proteins.
We introduce molecular and cellular criteria — based on morphology, ploidy, CpG island methylation and immune infiltration — that improve the characterization of malignant pleural mesothelioma. These criteria reveal adaptation strategies that are adopted by tumor cells and offer new possibilities for classification and clinical management.
A GWAS meta-analysis, combined with tracing the parental transmitted and non-transmitted alleles in parent–offspring pairs, enabled us to distinguish the effects of maternal and fetal genomes on gestational duration and their links with birth weight. The identified genes are more likely to be differentially expressed during labor and show signs of antagonistic pleiotropy with fetal genome effects on birth weight.
Adjusting for common variant polygenic scores improves yield in gene-based rare variant association tests for quantitative traits, particularly when using sparse mixed models or simple linear models as an alternative to dense mixed-model approaches.
This analysis of individuals of admixed genetic ancestries suggests that complex trait causal variant effect sizes are, by and large, similar across ancestries, and discusses the implications for the study of these and other diverse populations.
Genome-wide CRISPR screening identifies thymidine nucleotide metabolism as a key regulator of human telomere length. Thymidine supplementation promotes telomere elongation in cells derived from patients with telomere biology disorders.
A cross-ancestry genomic and transcriptomic cohort of gastric cancer highlights significantly mutated genes and mutational signatures, some of which are ancestry-specific.
Premalignant stromal cells from women with germline BRCA1 mutations exhibit increased expression of secreted factors regulating epithelial homeostasis in a paracrine fashion. These secreted factors, such as MMP3, promote premalignant epithelial changes including elevated proliferation and altered differentiation of a subpopulation of luminal progenitor cells.
Somatic evolutionary analysis of neuroblastoma, a pediatric tumor, proposes a common fetal time of origin. Notably, high-risk tumors exhibit early genomic instability and prolonged evolution, and this evolutionary duration predicts clinical outcomes.
Analysis of multiple tumor types, cancer cell lines and adult tissues identifies tumor-specific transposable-element-chimeric transcripts. Mass spectrometry data confirm that many are translated and subsequently located on the extracellular surface of cancer cells, highlighting potential immunogenic therapies.
Single-cell analysis of head and neck squamous cell carcinoma (HNSCC), specifically from human papillomavirus (HPV)-positive and HPV-negative oropharynx tumors, reveals high levels of inter- and intratumoral heterogeneity. Patterns of HPV gene expression were divergent within HPV-positive tumors, with corresponding functional effects on treatment resistance.
Transitional liver progenitor cells (TLPCs), which derive from biliary epithelial cells (BECs), differentiate into hepatocytes after serious liver damage. Notch and WNT/β-catenin signaling regulate BEC-to-TLPC and TLPC-to-hepatocyte conversions, respectively.
Genetic lineage tracing in mice shows that endocardium-derived fibroblasts preferentially proliferate in response to pressure overload. Ablation of these cells alleviates cardiac fibrosis and reduces functional decline after pressure overload injury.
Histone H2B N-terminus multisite lysine acetylation (H2BNTac) is identified as a signature of active enhancers. H2BNTac-positive putative enhancers are validated using orthogonal enhancer activity assays.
Disruption of MLL3/4 enzymatic activities prevents gastrulation and leads to early embryonic lethality in mice. This is largely due to defects in extraembryonic lineages, which compromise developmental progression.
Arabidopsis sperm cells exhibit widespread chromatin bivalency. Incorporation of histone variant H3.10 regulates sperm chromatin identity. In contrast, in vegetative cells, repressed genes are marked by H3K27me3, while pollination-related genes are active and marked by broad H3K4me3 domains.