Molecular Systems Biology最新文献

Craniofacial development is evolutionarily conserved, yet subtle changes in its regulatory network drive species-specific traits. Transposable elements (TEs) contribute to genome evolution, but their role in cranial neural crest cells (CNCCs) remains unclear. Here, we investigate the domestication of hominoid-specific TEs (LTR5Hs and SVAs) as enhancers during human CNCC specification, a process critical for vertebrate craniofacial development. Using human iPSC-derived CNCCs, we identified ~515 hominoid-specific TEs functioning as enhancers, including ~250 human-specific, predominantly LTR5Hs. These elements are enriched for CNCC coordinator motifs, are bound by the CNCC signature factor TWIST1, and their enhancer activity appears largely CNCC-specific. CRISPR-interference targeting ~75% of these active TEs led to widespread transcriptional dysregulation of genes involved in neural crest migration, and two orthogonal functional assays confirmed that CNCC migration is impaired upon TE repression. Finally, genes near human-specific TEs showed higher expression in human CNCCs compared to chimpanzee CNCCs, but TE repression restored gene expression to chimpanzee levels. These findings highlight how young TEs were domesticated to fine-tune CNCC regulatory networks, potentially contributing to lineage-specific craniofacial evolution.

African men are disproportionately impacted by aggressive prostate cancer (PCa). The key to this disparity is both genetic and environmental factors, alluding to epigenetic modifications. However, African-inclusive prostate tumour DNA methylation studies are lacking. Assembling a multi-geo-ancestral prostate tissue cohort, including men with (57 African, 48 European, 23 Asian) or without (65 African) PCa, we interrogate for genome-wide differential methylation. Overall, methylation appears to be driven by ancestry over geography (152 southern Africa, 41 Australia). African tumours show substantial heterogeneity, with universal hypermethylation indicating more pervasive epigenetic silencing, encompassing PCa suppressor genes and enhancer-targeted binding motifs. Conversely, African tumour-associated heterochromatic hypomethylation suggests chromatin relaxation and developmental pathway activation via enhancer targets. Notably, non-prostate lineage elements appeared preferentially exploited in African tumorigenesis, with ancestry potentially influencing the extent of lineage-inappropriate activation, and tumour progression marked by repression of developmental regulators. Together, these findings point to extensive epigenetic plasticity in African tumours, with intergenic regulatory remodelling promoting genomic instability, metastatic potential and aggressive disease phenotypes.

Proteomic techniques now measure thousands of proteins circulating in blood at population scale, but successful translation into clinically useful protein biomarkers is hampered by our limited understanding of their origins. Here, we use machine learning to systematically identify a median of 20 factors (range: 1-37) out of >1800 participant and sample charateristics that jointly explained an average of 19.4% (max. 100.0%) of the variance in plasma levels of ~3000 protein targets among 43,240 individuals. Proteins segregated into distinct clusters according to their explanatory factors, with modifiable characteristics explaining more variance compared to genetic variation (median: 10.0% vs 3.9%), and factors being largely consistent across the sexes and ancestral groups. We establish a knowledge graph that integrates our findings with genetic studies and drug characteristics to guide identification of potential drug target engagement markers. We demonstrate the value of our resource by identifying disease-specific biomarkers, like matrix metalloproteinase 12 for abdominal aortic aneurysm, and by developing a widely applicable framework for phenotype enrichment (R package: https://github.com/comp-med/r-prodente ). All results are explorable via an interactive web portal ( https://omicscience.org/apps/prot_foundation ).

Drug-tolerant cells to pro-apoptotic treatments exhibit transient resistance to subsequent challenges, which can be sustained via transcriptional and translational regulations. Although persister cells have been described in other cell death modalities, how they respond to subsequent treatments that are different from the one they originate from remains less explored. Here we show that drug-tolerant cells to pro-apoptotic treatments exhibit a reduced capacity to activate caspase-8, as well as higher levels of RIPK3 protein expression. As this apoptosis-tolerant cell state exhibits features of vulnerability to necroptosis, we show that alternating from apoptotic to necroptotic treatments increases cell response compared to drug holiday or sustained treatment. To gain insights on these transitions between states of vulnerability to cell death, we developed a compartmental model explaining the emergence of drug-tolerant cell populations, and the fluxes between drug-sensitivity states. We found that drug-sensitivity states coexist in a clonal population of cancer cells with continuous transitions between them, which are sufficient to explain both the sustained resistance to repeated treatments and how alternating drug treatments ameliorates the overall treatment efficacy.

Although asymptomatic malaria was historically perceived as innocuous, emerging evidence revealed an immunosuppressive signature induced by asymptomatic Plasmodium falciparum infections. To examine if a similar process occurs in Plasmodium vivax malaria, we pursued a systems approach, integrating transcriptional profiling together with previously reported and novel mass cytometry phenotypes from individuals with symptomatic and asymptomatic P. vivax malaria. Symptomatic P. vivax malaria featured upregulation of anti-inflammatory pathways and checkpoint receptors. A profound downregulation of transcripts with roles in monocyte function was observed in symptomatic P. vivax malaria. This reduction in monocyte transcriptional activity was accompanied by a significant depletion of CCR2⁺CXCR4⁺ classical monocytes in symptomatic individuals. Despite allowing transcriptional profiles supporting T-cell differentiation, dysregulation of genes associated with monocyte activation and the inflammasome was also evident in individuals carrying P. vivax asymptomatic infections. Our results identify monocyte dysregulation as a key feature of the response to P. vivax malaria and support the concept that asymptomatic infection is not innocuous and might not support all immune processes required to eliminate parasitemia or efficiently respond to vaccination.

Vascular sites have distinct susceptibility to atherosclerosis and aneurysm, yet the epigenomic and transcriptomic underpinning of vascular site-specific disease risk is largely unknown. Here, we performed single-cell chromatin accessibility (scATACseq) and gene expression profiling (scRNAseq) of mouse vascular tissue from three vascular sites. Through interrogation of epigenomic enhancers and gene regulatory networks, we discovered key regulatory enhancers to not only be cell type, but vascular site-specific. We identified epigenetic markers of embryonic origin including developmental transcription factors such as Tbx20, Hand2, Gata4, and Hoxb family members and discovered transcription factor motif accessibility to be vascular site-specific for smooth muscle, fibroblasts, and endothelial cells. We further integrated genome-wide association data for aortic dimension, and using a deep learning model to predict variant effect on chromatin accessibility, ChromBPNet, we predicted variant effects across cell type and vascular site of origin, revealing genomic regions enriched for specific TF motif footprints-including MEF2A, SMAD3, and HAND2. This work supports a paradigm that cell type and vascular site-specific enhancers govern complex genetic drivers of disease risk.

The complex interplay between circulating metabolites and immune responses, which is pivotal to disease pathophysiology, remains poorly understood and understudied in systematic research. Here, we performed a comprehensive analysis of the immune response and circulating metabolome in two Western European cohorts (534 and 324 healthy individuals) and one from sub-Saharan Africa (323 healthy donors). At the metabolic level, our analysis revealed sex-specific differences in the correlation between phosphatidylcholine and cytokine responses following ex vivo stimulation. Notably, sphingomyelin exhibited a significant negative correlation with monocyte-derived cytokine production in response to Staphylococcus aureus stimulation, a finding that was validated through functional experiments. Subsequently, using Mendelian randomization analysis, we established a link between sphingomyelin and COVID-19 severity, providing compelling evidence for its modulatory role in immune responses during human infection. Collectively, our results represent a unique resource ( https://lab-li.ciim-hannover.de/apps/imetabomap/ ) for exploring metabolic signatures associated with immune function in different populations, highlighting sphingomyelin metabolism as a potential target in treating inflammatory and infectious diseases.

Precise genome editing is crucial for functional studies and therapies. Base editors, while powerful, require optimization for efficiency. Meanwhile, emerging protein design methods and protein language models have driven efficient and intelligent protein engineering. In this study, we employed the Protein Mutational Effect Predictor (ProMEP) to predict the effects of single-site saturated mutations in Cas9 protein, using AncBE4max as the prototype to construct and test 18 candidate point mutations. Based on this, we further predicted combinations of multiple mutations and successfully developed a high-performance variant AncBE4max-AI-8.3, achieving a 2-3-fold increase in average editing efficiency. Introducing the engineered Cas9 into CGBE, YEE-BE4max, ABE-max, and ABE-8e improved their editing performance. The same strategy also substantially improves the efficiencies of HF-BEs. Stable enhancement in editing efficiency was also observed across seven cancer cell lines and human embryonic stem cells. In conclusion, we validated that AI models can serve as more effective protein engineering tools, providing a universal improvement strategy for a series of gene editing tools.

Immune-mediated inflammatory diseases remain plagued by poor treatment responses and lack curative therapies. Convergent findings suggest a role for the stromal compartment and extracellular matrix composition dysregulation. Using rheumatoid arthritis as a model, we define an analytical pipeline combining transcriptomic, proteomic and degradomic analysis to characterise disease activity-specific matrix perturbations. This revealed synergistic contributions from fibroblasts and myeloid cells to matrix composition, with fibroblast subsets defining distinct subsynovial niches through distinct matrix expression profiles. Transcriptional dysregulation of collagen VI was found to be a feature of RA activity, with collagen VI protein accumulation linked to remission-associated states. Spatial analysis and in vitro migration showed collagen VI inhibits immune ingress, confining infiltrating cells to perivascular pockets termed "COL6 dark" zones. Matrix degradation-associated monocytes were found at the leading edge of these zones, expanding immune-permissive niches, and releasing RA-associated collagen VI fragments. Our work reveals how dynamic matrix remodelling can in turn limit, and enable, cell immigration in RA, identifying a new mechanism controlling tissue-level disease activity.