Research Briefing

Leukocyte telomere length (LTL) has been associated with various health-related traits, with heterogeneity across specific demographic factors. Rich phenotypic and genomic data collected by the National Institutes of Health (NIH) All of Us Research Program from diverse US populations provided the opportunity to systematically assess the heterogeneity of the genomic, phenomic and geographic associations of LTL.

Through international collaboration and genetic analyses with short-read and long-read genome sequencing, an intronic repeat expansion in the GOLGA8A gene has been identified, with long CT-dimer-rich expansions strongly associated with a rare subtype of frontotemporal lobar degeneration.

The development of therapy-related myeloid neoplasms is a dangerous complication of cancer-directed therapy and is driven by the selection of hematopoietic cells with mutations in genes involved in the DNA damage response pathway. We show that short-term CDK4/6 inhibition mitigates clonal expansion of TP53-mutant hematopoietic cells during cytotoxic chemotherapy.

We constructed a super pangenome for the tomato, incorporating 20 newly assembled telomere-to-telomere (T2T) genomes and 27 previously published genomes. This comprehensive, genus-wide resource enables insight into tomato pan-centromere diversity and evolution, provides a catalog of structural variants and molecular markers linked to salinity tolerance, and led to the discovery of an immune receptor that confers resistance to fungal infection.

Oculopharyngodistal myopathy and oculopharyngeal myopathy with leukoencephalopathy are diseases caused by 50–200 repeats of the GGC DNA motif located in diverse sequences annotated as non-coding. This work shows that these repeats are embedded in previously unrecognized open reading frames, leading to their translation into novel and toxic polyglycine proteins.

By investigating single-cell gene expression and DNA methylation profiles of meningiomas, we found that the composition of the tumor microenvironment and cellular activation status both correlate with tumor aggressiveness. These findings explain the outcomes of previous DNA methylation-based classification approaches to meningioma and have direct clinical applicability.

Childhood brain tumors release antigens and cytokines into the cerebrospinal fluid that reprogram skull marrow toward the differentiation of myeloid cells and expansion of regulatory T cells; disrupting this tumor–marrow circuit collapses tolerance and induces tumor regression in vivo.

The three-dimensional (3D) organization of chromosomes is emerging as an important determinant of multiple cellular processes. We now show that 3D chromatin structures, maintained by the Polycomb complex, record epigenetic perturbation events.

Single-nucleus DNA sequencing analyses elucidated the heterogeneous evolution of the genomes of pancreatic cancer cells. The key features uncovered highlighted mechanisms of resistance to therapy that might support ongoing precision medicine efforts.

We developed DNA-Diffusion, a generative artificial intelligence (AI) method that creates synthetic regulatory elements showing enhanced activity. Multiple synthetic elements demonstrated superior cell-type-specific expression in computational predictions and episomal assays, and when integrated at AXIN2, a leukemia-protective gene, outperformed naturally occurring protective variants, opening new possibilities for precision gene therapies.

Primary mismatch repair-deficient gliomas are hypermutant but molecularly heterogeneous cancers with poor prognosis. We show that non-random mutational signatures cause somatic mutations in key glioma drivers that define genetic subgroups of this disease. Each subgroup harbors distinct mechanisms of genomic instability that shape their biological behaviors and immunotherapy responses.

The long-term contribution of human hematopoietic stem cell (HSC) clones to different blood lineages needs to be assessed under steady-state conditions over time. Using retrospective phylogenetic analysis and prospective clonal mutational tracing of all major blood lineages, we show that some HSC clones contribute stably to all lineages, while others show stable, intrinsically programmed lineage restriction.

We establish that adenine DNA methylation is widespread among unicellular eukaryotes, in which it marks transcriptionally active genes. This conserved pattern depends on the AMT1 enzyme, an ancestral eukaryotic adenine methyltransferase that has been recurrently lost in multicellular lineages, such as animals and plants.

Our study reveals how transforming growth factor-β (TGFβ) enables liver metastasis of colorectal cancer (CRC) in two ways: by limiting CD8⁺ T cell recruitment and inducing SPP1⁺ macrophages. Inhibition of TGFβ sensitizes tumors to PD-L1 blockade therapy, eradicating metastases in different CRC genetic models. Targeting SPP1 offers therapeutic benefit while avoiding the systemic effects of complete TGFβ inhibition.

We found that two key transcription factors contribute to disease progression in the classical subtype of pancreatic ductal adenocarcinoma. In the primary tumor context, the nuclear receptor HNF4G is the critical driver, but during the transition to metastasis, FOXA1 is derepressed and mediates metastatic potential.

Most aggressive metastatic prostate cancers are driven by activity of the androgen receptor (AR). This steroid-responsive transcription factor has a complex series of regulatory interactions with ligands, proteins and DNA that are required for normal biology and cancer phenotypes. We performed experiments to systematically identify genes required for maintaining AR protein levels, revealing mechanisms of regulating AR activity in the nucleus.

Evading elimination by the immune system is a hallmark of cancer, but the exact timing and pathways of immune evasion are still to be explored. Colorectal cancers were found to engage a combination of epigenetic, genetic and microenvironmental mechanisms, and establish immune evasion prior to their outgrowth.

We have discovered recurrent, somatic mutations in mitochondrial ribosomal RNA genes across all tumor types assessed. In contrast with the established idea that the majority of mitochondrial DNA molecules must be mutated to cause an effect, a low allelic dosage of these mutations disrupted mitochondrial protein translation, altering cancer metabolism and transcription.

Dilated cardiomyopathy (DCM) is more prevalent among individuals of African descent, but a genetic basis for this increased risk has remained unclear. By integrating genomic and phenotypic data from multiple African ancestry cohorts, we identified a common, ancestry-specific nonsense variant in CD36 that increases DCM risk by impairing myocardial energetics. This variant explains one-fifth of the excess DCM burden observed in individuals of African descent.

We developed a molecular tool that enables the loading of cohesin complexes at defined genomic regions in live cells. Use of this tool reveals that cohesin loop extrusion results in reduced gene expression and H3K27ac of sites in the TACL domains, thereby influencing the epigenetic composition of chromatin and the activity of genes within them.