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PubMed2026

Dual functional genomics reveals a broad and convergent landscape of asciminib resistance in BCR::ABL1.

BACKGROUND: Drug resistance is a constantly evolving challenge. The allosteric inhibitor asciminib is a novel therapy for chronic myelogenous leukemia (CML) that targets the myristoyl pocket of the BCR::ABL1 kinase. While it can overcome resistance to active-site inhibitors like imatinib, new resistance mutations to asciminib are emerging. The complete landscape of these mutations, particularly those outside the kinase domain or those arising from epistatic interactions between mutations, are not well understood. METHODS: This study employed a dual functional genomics approach in CML cell line models. A high-throughput adenosine base editing (ABE) screen was used to identify broad hotspots of asciminib resistance across the entire BCR::ABL1 protein. Deep mutational scanning (DMS) was then used to create a high-resolution map of all possible amino acid changes within these hotspots. An "edit-on-edit" screen was performed to investigate epistasis by introducing a library of mutations into a cell line that was pre-edited to incorporate the common imatinib-resistance mutation, Y253H. Finally, a novel Förster resonance energy transfer (FRET) biosensor was developed to measure the conformational state of BCR::ABL1 in live cells and link it to drug sensitivity. RESULTS: The screens identified 279 asciminib resistance mutations and revealed resistance hotspots distributed across the SH3, SH2, and kinase domains, in contrast to imatinib resistance, which is largely confined to the kinase domain. The study uncovered a potent epistatic interaction between a mutation in the SH3 domain (V73A) and a mutation in the kinase domain P-loop (Y253H), which synergistically conferred high-level resistance. The FRET biosensor demonstrated that asciminib resistance mutations tend to destabilize the "closed" inactive conformation of the ABL1 kinase. CONCLUSIONS: The landscape of asciminib resistance is broader and more complex than previously appreciated, involving mutations across multiple domains that disrupt ABL1 autoinhibition. Epistasis between mutations acquired during sequential therapies can create unexpected and potent resistance. However, these diverse genetic resistance mechanisms converge on a single biophysical measurement of the openness of the active ABL1 conformation. This provides a unified framework for understanding asciminib resistance and underscores the need for routine clinical resistance monitoring to include the SH3 and SH2 domains in first line and later line therapy.

Fusion Proteins, bcr-abl↗
PubMed2025

EucaMOD: a comprehensive multi-omics database for functional genomics research and molecular breeding of fast-growing eucalyptus trees.

Eucalyptus, one of the most widely planted plantation tree species globally, is primarily found in tropical and subtropical regions and contributes significantly to economic and social benefits. With advances in sequencing technologies, there is an increasing demand for the systematic analysis of multi-omics data among Eucalyptus species to enhance genetic breeding efforts. Although several early genomic databases have been established for eucalyptus, they have not been updated in a timely manner and lack recent multi-omics data, rendering them insufficient for current research needs. To address this gap, we developed the eucalyptus multi-omics database (EucaMOD, http://eucalyptusggd.net/eucamod), a comprehensive resource for cross-omics studies. In this study, we functionally annotated 45 eucalyptus genomes and structurally annotated 15, conducting comparative genomics and pan-proteomics analyses across all genomes. Additionally, we analyzed eucalyptus transcriptome, epigenome, and variome data through standardized workflows, enabling the in-depth mining and reanalysis of multi-omics datasets. EucaMOD is the most comprehensive multi-omics database for eucalyptus to date and includes data from 45 genomes (39 species), 870 mRNA-seq samples, 17 miRNA-seq samples, 52 epigenomic datasets (histone modifications and transcription factor binding), and genetic variation data from 1219 samples. To support functional genomics and molecular breeding research, the database is organized into the following 11 modules: Home, Species, Genomics, Comparative genomics, Pan-proteomics, Transcriptomics, Epigenetics, Variomics, Tools, Download, and Help. EucaMOD also offers online analysis tools for data mining, providing free public services to aid eucalyptus gene function and genetic engineering studies.

Eucalyptus↗
PubMed2025

Peering into the Bacterial Cell: From Transcription to Functional Genomics.

I started my faculty career in 1981 at the UW-Madison in the Department of Bacteriology and moved to the University of California, San Francisco in 1993, where I am a Professor in the Departments of Microbiology and Immunology and Cell and Tissue Biology. In this article, I first review my contributions to understanding the molecular biology of the bacterial transcriptional apparatus and the global role of alternative sigmas (σs), a major pillar of bacterial transcriptional control. I then discuss my role in spearheading the development of bacterial systems biology, specifically to the genome-wide phenotyping approaches necessary for rapid understanding of gene function and the molecular basis of pathway connections across the bacterial universe.

Genomics↗
PubMed2025

Functional genomic analysis of non-canonical DNA regulatory elements of the aryl hydrocarbon receptor.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor activated by environmental toxicants like halogenated and polycyclic aromatic hydrocarbons, which then binds to DNA and regulates gene expression. AHR is implicated in numerous physiological processes, including liver and immune function, cell cycle control, oncogenesis, and metabolism. Traditionally, AHR binds a consensus DNA sequence (GCGTG), the xenobiotic response element (XRE), recruits coregulators, and modulates gene expression. Yet, recent evidence suggests AHR can also regulate gene expression via a non-consensus sequence (GGGA), termed the non-consensus XRE (NC-XRE). The prevalence and functional significance of NC-XRE motifs in the genome have remained unclear. While ChIP and reporter studies hinted at AHR-NC-XRE interactions, direct evidence for transcriptional regulation in a native context was lacking. In this study, we analyzed AHR binding to NC-XRE sequences genome-wide in mouse liver, integrating ChIP-seq and RNA-seq data to identify candidate AHR target genes containing NC-XRE motifs in their regulatory regions. We found NC-XRE motifs in 82% of AHR-bound DNA, significantly enriched compared to random regions, and present in promoters and enhancers of AHR targets. Functional genomics on the Serpine1 gene revealed that deleting NC-XRE motifs reduced TCDD-induced Serpine1 upregulation, demonstrating direct regulation. These findings provide the first direct evidence for AHR-mediated regulation via NC-XRE in a natural genomic context, advancing our understanding of AHR-bound DNA and its impact on gene expression and physiological relevance.

Journal Article↗
PubMed2026

Engineering cold stress resilience in capsicum annuum through functional genomics and precision breeding.

This review synthesizes the molecular mechanisms of cold tolerance in pepper, integrating multi-omics data,genome editing, and precision breeding strategies to accelerate the development of cold-resilient cultivars. Cold stress is a significant environmental factor that affects the growth, productivity, and fruit quality of Capsicum annuum by impairing membrane integrity photosynthesis and cellular redox homeostasis. Although pepper has several endogenous cold-responsive regulators such as CaNAC035 and CabHLH035, along with antioxidant defense systems, its cold tolerance remains limited due to low transcriptional activation of key regulators, functional redundancy among cold-responsive genes, and the polygenicity of cold tolerance. These complexities, combined with low genetic diversity and linkage drag, have hindered the improvement of cold-resistant cultivars through conventional breeding. This review brings together the recent progress in understanding the molecular mechanisms of cold stress perception, signal transduction, transcriptional regulation, metabolic reprogramming, and phytohormone interactions in pepper. Precision Breeding 2.0 is a new innovation that combines the integration of multi-omics-based target identification with next-generation genome-editing techniques, allowing precise and multiplex engineering of complex and interconnected regulatory networks instead of single genes. We cover new approaches such as engineering the DREB/CBF pathway, allele-specific editing and targeted disruption of negative regulators to enhance the pathway(s) involved in cold response. Moreover, we propose a roadmap for integration of transcriptomics, proteomics, metabolomics, high-throughput phenomics, and speed breeding to accelerate the identification, validation, and deployment of superior alleles to boost cold tolerance. This review provides a foundation for developing climate-resilient pepper cultivars by connecting functional genomics with precision genome engineering approaches to maintain productivity under variable environmental conditions.

Capsicum↗
PubMed2005

AnoEST: toward A. gambiae functional genomics.

Here, we present an analysis of 215,634 EST and cDNA sequences of a major vector of human malaria Anopheles gambiae structured into the AnoEST database. The expressed sequences are grouped into clusters using genomic sequence as template and associated with inferred functional annotation, including the following: corresponding Ensembl gene prediction, putative orthologous genes in other species, homology to known proteins, protein domains, associated Gene Ontology terms, and corresponding classification into broad GO-slim functional groups. AnoEST is a vital resource for interpretation of expression profiles derived using recently developed A. gambiae cDNA microarrays. Using these cDNA microarrays, we have experimentally confirmed the expression of 7961 clusters during mosquito development. Of these, 3100 are not associated with currently predicted genes. Moreover, we found that clusters with confirmed expression are nonbiased with respect to the current gene annotation or homology to known proteins. Consequently, we expect that many as yet unconfirmed clusters are likely to be actual A. gambiae genes. [AnoEST is publicly available at http://komar.embl.de, and is also accessible as a Distributed Annotation Service (DAS).].

Animals↗
PubMed2025

Charting Postnatal Heart Development Using In Vivo Single-Cell Functional Genomics.

The transition at birth, marked by increased circulatory demands and rapid growth, necessitates extensive remodeling of the heart's structure, function, and metabolism. This transformation requires precise spatial and temporal coordination among diverse cardiac cell types; central to this process is cardiomyocyte maturation, yet the regulatory mechanisms driving these changes remain poorly understood. Here, we present a temporal and spatial atlas of postnatal hearts by integrating single-nucleus transcriptomics with image-based spatial transcriptomics, which uncovers the dynamic regulatory networks of cardiomyocyte maturation. To functionally interrogate candidate regulators in vivo , we developed Probe-based Indel-detectable Perturb-seq (PIP-seq), a high-throughput platform that uses probe-based chemistry to directly capture sgRNA expression, perturbation status, and transcriptomic profiles at single-nucleus resolution. Applying PIP-seq to postnatal cardiac development identified 21 novel regulators of cardiomyocyte maturation, highlighting critical nodal points in this process. Our study establishes a high-resolution framework for dissecting postnatal heart development, underscoring the integrative and highly ordered roles of microenvironment and intercellular communication in cardiomyocyte maturation. Importantly, PIP-seq enables systematic, high-throughput exploration of gene function and networks underlying complex biological processes in their native in vivo context.

Journal Article↗
PubMed2025

Design of highly functional genome editors by modelling CRISPR-Cas sequences.

Gene editing has the potential to solve fundamental challenges in agriculture, biotechnology and human health. CRISPR-based gene editors derived from microorganisms, although powerful, often show notable functional tradeoffs when ported into non-native environments, such as human cells1. Artificial-intelligence-enabled design provides a powerful alternative with the potential to bypass evolutionary constraints and generate editors with optimal properties. Here, using large language models2 trained on biological diversity at scale, we demonstrate successful precision editing of the human genome with a programmable gene editor designed with artificial intelligence. To achieve this goal, we curated a dataset of more than 1 million CRISPR operons through systematic mining of 26 terabases of assembled genomes and metagenomes. We demonstrate the capacity of our models by generating 4.8× the number of protein clusters across CRISPR-Cas families found in nature and tailoring single-guide RNA sequences for Cas9-like effector proteins. Several of the generated gene editors show comparable or improved activity and specificity relative to SpCas9, the prototypical gene editing effector, while being 400 mutations away in sequence. Finally, we demonstrate that an artificial-intelligence-generated gene editor, denoted as OpenCRISPR-1, exhibits compatibility with base editing. We release OpenCRISPR-1 to facilitate broad, ethical use across research and commercial applications.

CRISPR-Cas Systems↗
PubMed2026

Functional genomic screens uncover FERMT2 as a critical regulator of YAP/TAZ-driven tumorigenicity.

YAP and TAZ are transcriptional regulators essential for mechanotransduction, development, and tissue homeostasis, whose dysregulation is implicated in multiple diseases, including cancer. To identify key regulators of YAP/TAZ signaling required for breast cancer cell fitness, we performed CRISPR/Cas9-based loss-of-function genetic screens both in vitro and in vivo. A custom sgRNA library targeting 216 candidate YAP/TAZ modulators was screened across three breast cancer cell lines. Among these, FERMT2, a component of the integrin signaling pathway, consistently emerged as a strong drop-out hit, highlighting its essential role in sustaining YAP/TAZ-dependent fitness. Bioinformatic analysis of large-scale cancer datasets further revealed genetic co-dependency between FERMT2, YAP, and TAZ, particularly in tumors with high YAP/TAZ expression. Functional validation through FERMT2 knockout and silencing demonstrated its requirement for proliferation, anchorage-independent growth, and tumorigenicity in triple-negative breast cancer cells. FERMT2 loss impaired YAP/TAZ nuclear accumulation, reduced the expression of YAP/TAZ target genes, and decreased phosphorylation at key tyrosine residues. Mechanistically, FERMT2 regulates YAP/TAZ independently of the canonical Hippo pathway through integrin-mediated activation of FAK. Consistent with this, glucocorticoid-driven FAK activation restored YAP/TAZ signaling in FERMT2-depleted cells. Partial epistasis analyses also indicate that FERMT2 modulates actin-dependent regulation of YAP/TAZ. Together, these findings identify FERMT2 as a pivotal upstream regulator of YAP/TAZ via FAK signaling, demonstrate that YAP/TAZ are principal effectors of integrin activity, and suggest that FERMT2 may represent a selective vulnerability in cancers with elevated YAP/TAZ signaling.

Humans↗
PubMed2026

Unravelling the biological nexus of smoking and postpartum depression: a meta-analysis and functional genomics approach.

PURPOSE: Postpartum depression (PPD) is a prevalent psychological condition among birthing women. While several psycho-socio-economic and neurobiological factors influence its development, its relationship with smoking behavior and nicotine addiction remains largely inconclusive. METHODS: In this combinatorial study, we first evaluate the relationship between smoking and depressive behaviors in postpartum women using data extracted from pertinent primary epidemiological studies. Additionally, to discern the molecular and cellular mechanisms underlying this association, we identified common genetic elements and evaluated their functional attributes using in silico analyses. RESULTS: Meta-analytical assessment of systematically collected data from 38 studies indicated that smoking women are twice as likely to develop PPD, compared to their non-smoking counterparts. While geocultural attributes did not affect this relationship, timing of smoking was a significant moderator, with current and gestational smoking statuses being more strongly linked with PPD outcome, compared to the past smoking habit. Further, depression scores in smoking postpartum women were higher than those in non-smoking controls. Analysis of the common protein-encoding genes underlying the pathophysiology of nicotine addiction and PPD revealed several critical hub proteins (viz., AKT1, JUN, CTNNB1, PTEN, EGFR, ESR1, SRC, STAT3, FN1, IL1B, IL6, TNF, TP53, GAPDH, INS, MYC, and ALB) which were predicted to alter multiple pathophysiological pathways associated with transcriptional expression, intra- and intercellular signaling transduction, metabolism, and immune functions. CONCLUSION: Our results indicate that smoking is strongly associated with depressive behavior in postpartum women, although this association involve mediation of additional environmental and psychosocial elements. Moreover, network analysis of common genetic elements identified several potentially disrupted neurophysiological pathways in postpartum women with smoking and depressive behaviors which may aid in characterizing the underlying relationship between the two conditions.

Humans↗
PubMed2026

Integrative transcriptomic, spatial and functional-genomic analysis identifies a UFMylation-related vascular-stromal program and prioritizes WWTR1 in glioblastoma.

Glioblastoma (GBM) contains spatially organized stress-adaptive and vascular niches. Because transcript abundance does not measure UFM1 conjugation, we asked whether a UFMylation-related transcriptional axis identifies a reproducible tissue program and alters candidate prioritization. In 518 unique primary TCGA-GBM tumors profiled on the Affymetrix HT Human Genome U133A array, weighted gene co-expression network analysis of 8,000 variable genes yielded 12 modules. The 278-gene green module ranked first across nine prespecified traits (mean |r|=0.637). Direct overlap comprised 1/3 measurable UFMylation-core, 5/19 ER-stress/UPR, and 2/15 proteostasis genes; after excluding overlapping genes, correlations with the green eigengene remained significant (r = 0.373, 0.831, 0.639, and 0.699 for UFMylation-core, ER-stress/UPR, proteostasis, and composite scores, respectively). The green score was associated with overall survival per standard-deviation increase (HR 1.17, 95% CI 1.07-1.28), although clinical adjustment attenuated the estimate. In a 10-sample single-cell dataset, sample-level scores were higher in pericytes and endothelial cells than in malignant cells. Donor-aware IvyGAP analysis supported regional organization, whereas one Visium section showed stronger concordance with ER-stress/UPR and mesenchymal scores than with the UFMylation-core score. CellChat indicated pathway-selective rather than global remodeling of inferred vascular communication. Layer ablation moved WWTR1 from rank 48 using WGCNA alone to rank 4 overall and rank 1 among non-common-essential genes after cross-platform integration. These findings define an ER-stress/mesenchymal-weighted, UFMylation-related vascular-stromal transcriptional association and nominate WWTR1 for experimental testing.

Humans↗
PubMed2025

The extracellular vesicle transcriptome provides tissue-specific functional genomic annotation relevant to disease susceptibility in obesity.

We characterized circulating extracellular vesicles (EVs) in obese and lean humans, identifying transcriptional cargo differentially expressed in obesity (277 unique genes; false discovery rate < 10%). Since circulating EVs may have broad origin, we compared this obesity EV transcriptome with expression from human visceral-adipose-tissue-derived EVs from freshly collected and cultured biopsies from the same obese individuals, observing high concordance. Using a comprehensive set of adipose-specific epigenomic and chromatin conformation assays, we found that the differentially expressed transcripts from the EVs were those regulated in adipose by body mass index-associated SNPs (p < 5 &#xd7; 10-8) from a large-scale genome-wide association study (GWAS). Using a phenome-wide association study of the regulatory SNPs for the EV-derived transcripts, we identified a substantial enrichment for inflammatory phenotypes, including type 2 diabetes. Collectively, these findings represent the convergence of the GWAS (genetics), epigenomics (transcript regulation), and EV (liquid biopsy) fields, enabling powerful future genomic studies of complex diseases.

Humans↗
PubMed2003

Genetics and functional genomics of type 2 diabetes mellitus.

Genome-wide studies of transcription in the skeletal muscle of type 2 diabetic patients have identified coordinated changes in the expression of genes involved in oxidative phosphorylation, and have underlined the central role of the oxidative-phosphorylation regulator, PCG1alpha. These findings help unravel the complex pathogenesis and inheritance of polygenic type 2 diabetes mellitus.

Animals↗
PubMed2025

Functional genomics of trypanotolerant and trypanosusceptible cattle infected with Trypanosoma congolense across multiple time points and tissues.

Human African trypanosomiasis (HAT), or sleeping sickness, is a neglected tropical disease caused by infection with trypanosome parasites (Trypanosoma spp.). These are transmitted by infected tsetse flies (Glossina spp.) and cause a similar disease in animals, known as African animal trypanosomosis (AAT), which is one of the largest constraints to livestock production in sub-Saharan Africa and causes a financial burden of approximately $4.5 billion annually. Some African Bos taurus cattle populations have an important evolutionary adaptation known as trypanotolerance, a genetically determined tolerance of infection by trypanosome parasites (Trypanosoma spp.). Trypanotolerant African B. taurus N'Dama and trypanosusceptible Bos indicus Boran cattle responded in largely similar ways during trypanosome infection when gene expression was examined using blood, liver, lymph node, and spleen samples with peaks and troughs of gene expression differences following the cyclic pattern of parasitaemia exhibited during trypanosome infection. However, differences in response to infection between the two breeds were reflected in differential expression of genes related to the immune system such as those encoding antimicrobial peptides and cytokines, including, for example, the antimicrobial peptide encoding genes LEAP2, CATHL3, DEFB4A, and S100A7 and the cytokine genes CCL20, CXCL11, CXCL13, CXCL16, CXCL17, IL33, and TNFSF13B. In addition, transcriptional profiling of peripheral blood identified expression differences in genes relating to coagulation and iron homeostasis, which supports the hypothesis that the dual control of parasitaemia and the anaemia resulting from the innate immune response to trypanosome parasites is key to trypanotolerance and provide new insights into the molecular mechanisms underlying this phenomenon.

Animals↗
PubMed2026

Predicting genome-wide functional constraints with GPN-Star.

Genomic language models have emerged as a powerful approach for learning genome-wide functional constraints directly from DNA sequences1. However, standard genomic language models adapted from natural language processing often require large model sizes and computational resources, yet still fall short of classical evolutionary models in predictive tasks2-4. Here we introduce a genomic pretrained network with species tree and alignment representations (GPN-Star), which is a biologically grounded genomic language model featuring a phylogeny-aware architecture that leverages whole-genome alignments and species trees to model evolutionary relationships explicitly. Trained on alignments spanning vertebrate, mammal and primate evolutionary timescales, GPN-Star achieves state-of-the-art performance across a wide range of variant effect prediction tasks in both coding and non-coding regions of the human genome. Analyses across timescales show task-dependent advantages of modelling more recent versus deeper evolution. To demonstrate its potential to advance human genetics, we show that GPN-Star substantially outperforms previous methods in prioritizing pathogenic and fine-mapped genome-wide association study variants, yields strong enrichments of complex trait heritability and improves power in rare variant association testing5. Extending beyond humans, we train GPN-Star for five model organisms-Mus musculus, Gallus gallus, Drosophila melanogaster, Caenorhabditis elegans and Arabidopsis thaliana-demonstrating the robustness and generalizability of the framework. Taken together, these results position GPN-Star as a scalable, powerful and flexible tool for genome interpretation, well suited to leverage the growing abundance of comparative genomics data.

Journal Article↗
PubMed2023

DisP-seq reveals the genome-wide functional organization of DNA-associated disordered proteins.

Intrinsically disordered regions (IDRs) in DNA-associated proteins are known to influence gene regulation, but their distribution and cooperative functions in genome-wide regulatory programs remain poorly understood. Here we describe DisP-seq (disordered protein precipitation followed by DNA sequencing), an antibody-independent chemical precipitation assay that can simultaneously map endogenous DNA-associated disordered proteins genome-wide through a combination of biotinylated isoxazole precipitation and next-generation sequencing. DisP-seq profiles are composed of thousands of peaks that are associated with diverse chromatin states, are enriched for disordered transcription factors (TFs) and are often arranged in large lineage-specific clusters with high local concentrations of disordered proteins and different combinations of histone modifications linked to regulatory potential. We use DisP-seq to analyze cancer cells and reveal how disordered protein-associated islands enable IDR-dependent mechanisms that control the binding and function of disordered TFs, including oncogene-dependent sequestration of TFs through long-range interactions and the reactivation of differentiation pathways upon loss of oncogenic stimuli in Ewing sarcoma.

DNA↗