Research Briefing

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.

In this study, we uncover the critical role of p300/CBP-mediated histone H2B N terminus multisite lysine acetylation (H2BNTac) in defining oncogenic enhanceosomes in prostate cancer. Degradation of p300/CBP rapidly disables H2BNTac-marked oncogenic enhancers and represents a promising therapeutic strategy for enhancer-driven malignancies, including prostate cancer.

We used a massively parallel reporter assay (MPRA) to test thousands of autoimmune disease-associated genetic variants for allele-specific effects on gene expression in primary human T cells. Variants that altered gene expression within our MPRA were then linked to T cell regulatory networks and proliferation using bulk and single-cell CRISPR-interference screens.

GSL5, a glucan synthase, acts as a suppressor of jasmonic acid-mediated immunity in cruciferous plants. Inactivation of GSL5 by genome editing confers high-level and broad-spectrum resistance to pathogens that cause clubroot disease in four cruciferous species.

Tamoxifen is an essential drug in breast cancer therapy. Unlike prevailing models of therapy-related tumorigenesis, tamoxifen acts by directly activating the PI3K pathway, bypassing the need for mutations in one of the most common driver genes in sporadic uterine cancer. These findings open avenues for investigating similar mechanisms in other drugs.

We combined CRISPR activation of all 1,836 known human transcription factors with high-throughput Perturb-seq to recreate the diverse transcriptional states occupied by fibroblasts in vivo. Our study revealed regulators of key states and showed that inducing normal states can, in some cases, suppress those linked to disease.

Rice sheath blight is a major fungal disease caused by the necrotrophic pathogen Rhizoctonia solani. We identified a natural SBRR1-R allele that is activated by the bHLH57 transcription factor, leading to increased expression of chitinase antifungal protein genes that confer resistance to sheath blight.

We show that alternative DNA structures, called G-quadruplexes, behave as elements of eukaryotic promoters. Our data suggest that they function to support intrinsic nucleosome exclusion and to facilitate transcriptional pause release by RNA polymerase II.

Transposable elements (TEs) are important in the evolution of genomic functions but the mechanisms of their precise role in cancer pathogenesis is unclear. Alternative promoters at the TE subclass long terminal repeats (LTRs) are activated when topologically associating domain (TAD) hierarchy maintained by NIPBL is lost, potentially leading to aberrant transcription of oncogenes.

We created a population-scale functional genomic dataset that maps whole blood regulatory variation in three South African groups. This resource supports the interpretation of genome-wide association studies in African-ancestry individuals, enabling translation to actionable discoveries.