bims-ginsta Biomed News
on Genome instability
Issue of 2024–12–22
thirteen papers selected by
Jinrong Hu, National University of Singapore
  1. Spatial transcriptomic clocks reveal cell proximity effects in brain ageing.
  2. Engineered extrachromosomal oncogene amplifications promote tumorigenesis.
  3. Timely TGFβ signalling inhibition induces notochord.
  4. Isolation and manipulation of meiotic spindles from mouse oocytes reveals migration regulated by pulling force during asymmetric division.
  5. Spatial organizations of heterochromatin underpin nuclear structural integrity of ventricular cardiomyocytes against mechanical stress.
  6. Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration.
  7. Integrative analysis of the 3D genome and epigenome in mouse embryonic tissues.
  8. Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer.
  9. Binding site maturation modulated by molecular density underlies Ndc80 binding to kinetochore receptor CENP-T.
  10. Hierarchical design of pseudosymmetric protein nanocages.
  11. Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing.
  12. Cardiac Reprogramming and Gata4 Overexpression Reduce Fibrosis and Improve Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.
  13. Four-component protein nanocages designed by programmed symmetry breaking.
  1. Nature. 2024 Dec 18.
    Spatial transcriptomic clocks reveal cell proximity effects in brain ageing.
    Eric D Sun, Olivia Y Zhou, Max Hauptschein, Nimrod Rappoport, Lucy Xu, Paloma Navarro Negredo, Ling Liu, Thomas A Rando, James Zou, Anne Brunet.
      Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk1. Brain ageing is complex and is accompanied by many cellular changes2. Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions-exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types. Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell-cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.
    DOI:  https://doi.org/10.1038/s41586-024-08334-8
  2. Nature. 2024 Dec 18.
    Engineered extrachromosomal oncogene amplifications promote tumorigenesis.
    Davide Pradella, Minsi Zhang, Rui Gao, Melissa A Yao, Katarzyna M Gluchowska, Ylenia Cendon-Florez, Tanmay Mishra, Gaspare La Rocca, Moritz Weigl, Ziqi Jiao, Hieu H M Nguyen, Marta Lisi, Mateusz M Ozimek, Chiara Mastroleo, Kevin Chen, Felix Grimm, Jens Luebeck, Shu Zhang, Andrea Alice Zolli, Eric G Sun, Bhargavi Dameracharla, Zhengqiao Zhao, Yuri Pritykin, Carlie Sigel, Howard Y Chang, Paul S Mischel, Vineet Bafna, Cristina R Antonescu, Andrea Ventura.
      Focal gene amplifications are among the most common cancer-associated mutations1 but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy to engineer large (more than 1 Mbp) focal amplifications mediated by extrachromosomal DNAs (ecDNAs)2 in a spatiotemporally controlled manner in cells and in mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures. We also apply this approach to generate mice harbouring Cre-inducible Myc- and Mdm2-containing ecDNAs analogous to those occurring in human cancers. We show that the engineered ecDNAs spontaneously accumulate in primary cells derived from these animals, promoting their proliferation, immortalization and transformation. Finally, we demonstrate the ability of Mdm2-containing ecDNAs to promote tumour formation in an autochthonous mouse model of hepatocellular carcinoma. These findings offer insights into the role of ecDNA-mediated gene amplifications in tumorigenesis. We anticipate that this approach will be valuable for investigating further unresolved aspects of ecDNA biology and for developing new preclinical immunocompetent mouse models of human cancers harbouring specific focal gene amplifications.
    DOI:  https://doi.org/10.1038/s41586-024-08318-8
  3. Nature. 2024 Dec 18.
    Timely TGFβ signalling inhibition induces notochord.
    Tiago Rito, Ashley R G Libby, Madeleine Demuth, Marie-Charlotte Domart, Jake Cornwall-Scoones, James Briscoe.
      The formation of the vertebrate body involves the coordinated production of trunk tissues from progenitors located in the posterior of the embryo. Although in vitro models using pluripotent stem cells replicate aspects of this process1-10, they lack crucial components, most notably the notochord-a defining feature of chordates that patterns surrounding tissues11. Consequently, cell types dependent on notochord signals are absent from current models of human trunk formation. Here we performed single-cell transcriptomic analysis of chick embryos to map molecularly distinct progenitor populations and their spatial organization. Guided by this map, we investigated how differentiating human pluripotent stem cells develop a stereotypical spatial organization of trunk cell types. We found that YAP inactivation in conjunction with FGF-mediated MAPK signalling facilitated WNT pathway activation and induced expression of TBXT (also known as BRA). In addition, timely inhibition of WNT-induced NODAL and BMP signalling regulated the proportions of different tissue types, including notochordal cells. This enabled us to create a three-dimensional model of human trunk development that undergoes morphogenetic movements, producing elongated structures with a notochord and ventral neural and mesodermal tissues. Our findings provide insights into the mechanisms underlying vertebrate notochord formation and establish a more comprehensive in vitro model of human trunk development. This paves the way for future studies of tissue patterning in a physiologically relevant environment.
    DOI:  https://doi.org/10.1038/s41586-024-08332-w
  4. bioRxiv. 2024 Dec 08. pii: 2024.12.06.627260. [Epub ahead of print]
    Isolation and manipulation of meiotic spindles from mouse oocytes reveals migration regulated by pulling force during asymmetric division.
    Ning Liu, Ryo Kawamura, Wenan Qiang, Ahmed Balboula, John F Marko, Huanyu Qiao.
      Spindles are essential for accurate chromosome segregation in all eukaryotic cells. This study presents a novel approach for isolating fresh mammalian spindles from mouse oocytes, establishing it as a valuable in vitro model system for a wide range of possible studies. Our method enables the investigation of the physical properties and migration force of meiotic spindles in oocytes. We found that the spindle length decreases upon isolation from the oocyte. Combining this observation with direct measurements of spindle mechanics, we examined the forces governing spindle migration during oocyte asymmetric division. Our findings suggest that the spindle migration is regulated by a pulling force and a net tensile force of approximately 680 pN is applied to the spindle in vivo during the migration process. This method, unveiling insights into spindle dynamics, holds promise as a robust model for future investigations into spindle formation and chromosome separation. We also found that the same approach could not isolate spindles from somatic cells, indicative of mammalian oocytes having a unique spindle organization amenable to isolation.
    DOI:  https://doi.org/10.1101/2024.12.06.627260
  5. Cell Rep. 2024 Dec 09. pii: S2211-1247(24)01399-8. [Epub ahead of print]43(12): 115048
    Spatial organizations of heterochromatin underpin nuclear structural integrity of ventricular cardiomyocytes against mechanical stress.
    Keita Fujiwara, Tadashi Inoue, Aya Kimoto, Jiang Zixian, Keizo Tokuhiro, Yoshiki Yasukochi, Tomoya O Akama, Chen-Leng Cai, Ichiro Shiojima, Hiroshi Kimura, Shige H Yoshimura, Tomoyuki Nakamura, Maretoshi Hirai.
      Cardiomyocyte (CM) nuclei are constantly exposed to mechanical stress, but how they maintain their nuclear shape remains unknown. In this study, we found that ventricular CM nuclei acquire characteristic prominent spatial organizations of heterochromatin (SOH), which are disrupted by high-level expression of H2B-mCherry in mice. SOH disruption was associated with nuclear softening, leading to extreme elongation and rupture under unidirectional mechanical stress. Loosened chromatin then leaks into the cytosol, causing severe inflammation and cardiac dysfunction. Although SOH disruption was accompanied by loosened higher-order genomic structures, the change in gene expression before nuclear deformation was mild, suggesting that SOH play major roles in nuclear structural integrity. Aged CM nuclei consistently exhibited scattered SOH and marked elongation. Furthermore, we provide mechanistic insight into the development and maintenance of SOH driven by chromatin compaction and condensate formation. These results highlight SOH as a safeguard of nuclear shape and genomic integrity against mechanical stress.
    Keywords:  CP: Cell biology; aging; cGAS/STING; cardiomyocyte; chromatin compaction; heart failure; heterochromatin; higher-order genomic structures; histone H1; mechanical stress; nuclear shape
    DOI:  https://doi.org/10.1016/j.celrep.2024.115048
  6. Cell. 2024 Nov 26. pii: S0092-8674(24)01311-4. [Epub ahead of print]
    Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration.
    Han Chen, Chao Liu, Shiyao Cui, Yingqian Xia, Ke Zhang, Hanxiao Cheng, Jingyu Peng, Xiaoling Yu, Luyang Li, Hualin Yu, Jufang Zhang, Ju-Sheng Zheng, Bing Zhang.
      Intermittent fasting has gained global popularity for its potential health benefits, although its impact on somatic stem cells and tissue biology remains elusive. Here, we report that commonly used intermittent fasting regimens inhibit hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). This effect is independent of calorie reduction, circadian rhythm alterations, or the mTORC1 cellular nutrient-sensing mechanism. Instead, fasting activates crosstalk between adrenal glands and dermal adipocytes in the skin, triggering the rapid release of free fatty acids into the niche, which in turn disrupts the normal metabolism of HFSCs and elevates their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. A randomized clinical trial (NCT05800730) indicates that intermittent fasting inhibits human hair growth. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration and identifies interorgan communication that eliminates activated HFSCs and halts tissue regeneration during periods of unstable nutrient supply.
    Keywords:  hair follicle regeneration; hair follicle stem cells; hair growth; intermittent fasting; somatic stem cells
    DOI:  https://doi.org/10.1016/j.cell.2024.11.004
  7. Nat Struct Mol Biol. 2024 Dec 16.
    Integrative analysis of the 3D genome and epigenome in mouse embryonic tissues.
    Miao Yu, Nathan R Zemke, Ziyin Chen, Ivan Juric, Rong Hu, Ramya Raviram, Armen Abnousi, Rongxin Fang, Yanxiao Zhang, David U Gorkin, Yang E Li, Yuan Zhao, Lindsay Lee, Shreya Mishra, Anthony D Schmitt, Yunjiang Qiu, Diane E Dickel, Axel Visel, Len A Pennacchio, Ming Hu, Bing Ren.
      While a rich set of putative cis-regulatory sequences involved in mouse fetal development have been annotated recently on the basis of chromatin accessibility and histone modification patterns, delineating their role in developmentally regulated gene expression continues to be challenging. To fill this gap, here we mapped chromatin contacts between gene promoters and distal sequences across the genome in seven mouse fetal tissues and across six developmental stages of the forebrain. We identified 248,620 long-range chromatin interactions centered at 14,138 protein-coding genes and characterized their tissue-to-tissue variations and developmental dynamics. Integrative analysis of the interactome with previous epigenome and transcriptome datasets from the same tissues revealed a strong correlation between the chromatin contacts and chromatin state at distal enhancers, as well as gene expression patterns at predicted target genes. We predicted target genes of 15,098 candidate enhancers and used them to annotate target genes of homologous candidate enhancers in the human genome that harbor risk variants of human diseases. We present evidence that schizophrenia and other adult disease risk variants are frequently found in fetal enhancers, providing support for the hypothesis of fetal origins of adult diseases.
    DOI:  https://doi.org/10.1038/s41594-024-01431-2
  8. J Clin Invest. 2024 Dec 17. pii: e183353. [Epub ahead of print]
    Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer.
    Yuri Kim, Seong Won Kim, David Saul, Meraj Neyazi, Manuel Schmid, Hiroko Wakimoto, Neil Slaven, Joshua H Lee, Olivia G Layton, Lauren K Wasson, Justin H Letendre, Feng Xiao, Jourdan K Ewoldt, Konstantinos Gkatzis, Peter Sommer, Bénédicte Gobert, Nicolas Wiest-Daesslé, Quentin McAfee, Nandita Singhal, Mingyue Lun, Joshua M Gorham, Zoltan Arany, Arun Sharma, Christopher N Toepfer, Gavin Y Oudit, William T Pu, Diane E Dickel, Len A Pennacchio, Axel Visel, Christopher S Chen, J G Seidman, Christine E Seidman.
      Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure. To understand mechanisms that regulate abundant cardiomyocyte TTN expression we characterized highly conserved intron 1 sequences that exhibited dynamic changes in chromatin accessibility during differentiation of human cardiomyocytes from induced pluripotent stem cells (hiPSC-CMs). Homozygous deletion of these sequences in mice caused embryonic lethality while heterozygous mice demonstrated allele-specific reduction in Ttn expression. A 296 bp fragment of this element, denoted E1, was sufficient to drive expression of a reporter gene in hiPSC-CMs. Deletion of E1 downregulated TTN expression, impaired sarcomerogenesis, and decreased contractility in hiPSC-CMs. Site-directed mutagenesis of predicted NKX2-5- and MEF2-binding sites within E1 abolished its transcriptional activity. Embryonic mice expressing E1 reporter gene constructs validated in vivo cardiac-specific activity of E1 and the requirement for NKX2-5 and MEF2 binding sequences. Moreover, isogenic hiPSC-CMs containing a rare E1 variant in the predicted MEF2 binding motif that was identified in a patient with unexplained DCM showed reduced TTN expression. Together these discoveries define an essential, functional enhancer that regulates TTN expression. Manipulation of this element may advance therapeutic strategies to treat DCM caused by TTN haploinsufficiency.
    Keywords:  Cardiology; Cardiovascular disease; Genetic diseases; Genetics; Heart failure
    DOI:  https://doi.org/10.1172/JCI183353
  9. Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2401344121
    Binding site maturation modulated by molecular density underlies Ndc80 binding to kinetochore receptor CENP-T.
    Ekaterina V Tarasovetc, Gunter B Sissoko, Aleksandr Maiorov, Anna S Mukhina, Fazoil I Ataullakhanov, Iain M Cheeseman, Ekaterina L Grishchuk.
      Macromolecular assembly depends on tightly regulated pairwise binding interactions that are selectively favored at assembly sites while being disfavored in the soluble phase. This selective control can arise due to molecular density-enhanced binding, as recently found for the kinetochore scaffold protein CENP-T. When clustered, CENP-T recruits markedly more Ndc80 complexes than its monomeric counterpart, but the underlying molecular basis remains elusive. Here, we use quantitative in vitro assays to reveal two distinct mechanisms driving this behavior. First, Ndc80 binding to CENP-T is a two-step process: initially, Ndc80 molecules rapidly associate and dissociate from disordered N-terminal binding sites on CENP-T. Over time, these sites undergo maturation, resulting in stronger Ndc80 retention. Second, we find that this maturation transition is regulated by a kinetic barrier that is sensitive to the molecular environment. In the soluble phase, binding site maturation is slow, but within CENP-T clusters, this process is markedly accelerated. Notably, the two Ndc80 binding sites in human CENP-T exhibit distinct maturation rates and environmental sensitivities, which correlate with their different amino acid content and predicted binding conformations. This clustering-induced maturation is evident in dividing human cells, suggesting a distinct regulatory entry point for controlling kinetochore assembly. We propose that the tunable acceleration of binding site maturation by molecular crowding may represent a general mechanism for promoting the formation of macromolecular structures.
    Keywords:  binding site maturation; kinetic barrier; kinetochore; molecular density; single-molecule binding assay
    DOI:  https://doi.org/10.1073/pnas.2401344121
  10. Nature. 2024 Dec 18.
    Hierarchical design of pseudosymmetric protein nanocages.
    Quinton M Dowling, Young-Jun Park, Chelsea N Fries, Neil C Gerstenmaier, Sebastian Ols, Erin C Yang, Adam J Wargacki, Annie Dosey, Yang Hsia, Rashmi Ravichandran, Carl D Walkey, Anika L Burrell, David Veesler, David Baker, Neil P King.
      Discrete protein assemblies ranging from hundreds of kilodaltons to hundreds of megadaltons in size are a ubiquitous feature of biological systems and perform highly specialized functions1,2. Despite remarkable recent progress in accurately designing new self-assembling proteins, the size and complexity of these assemblies has been limited by a reliance on strict symmetry3. Here, inspired by the pseudosymmetry observed in bacterial microcompartments and viral capsids, we developed a hierarchical computational method for designing large pseudosymmetric self-assembling protein nanomaterials. We computationally designed pseudosymmetric heterooligomeric components and used them to create discrete, cage-like protein assemblies with icosahedral symmetry containing 240, 540 and 960 subunits. At 49, 71 and 96 nm diameter, these nanocages are the largest bounded computationally designed protein assemblies generated to date. More broadly, by moving beyond strict symmetry, our work substantially broadens the variety of self-assembling protein architectures that are accessible through design.
    DOI:  https://doi.org/10.1038/s41586-024-08360-6
  11. Nature. 2024 Dec 18.
    Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing.
    Qi Qu, Yan Chen, Yu Wang, Weiche Wang, Shating Long, Heng-Ye Yang, Jianfeng Wu, Mengqi Li, Xiao Tian, Xiaoyan Wei, Yan-Hui Liu, Shengrong Xu, Jinye Xiong, Chunyan Yang, Zhenhua Wu, Xi Huang, Changchuan Xie, Yaying Wu, Zheni Xu, Cixiong Zhang, Baoding Zhang, Jin-Wei Feng, Junjie Chen, Yuanji Feng, Huapan Fang, Liyun Lin, Z K Xie, Beibei Sun, Huayu Tian, Yong Yu, Hai-Long Piao, Xiao-Song Xie, Xianming Deng, Chen-Song Zhang, Sheng-Cai Lin.
      Lithocholic acid (LCA) is accumulated in mammals during calorie restriction and it can activate AMP-activated protein kinase (AMPK) to slow down ageing1. However, the molecular details of how LCA activates AMPK and induces these biological effects are unclear. Here we show that LCA enhances the activity of sirtuins to deacetylate and subsequently inhibit vacuolar H+-ATPase (v-ATPase), which leads to AMPK activation through the lysosomal glucose-sensing pathway. Proteomics analyses of proteins that co-immunoprecipitated with sirtuin 1 (SIRT1) identified TUB-like protein 3 (TULP3), a sirtuin-interacting protein2, as a LCA receptor. In detail, LCA-bound TULP3 allosterically activates sirtuins, which then deacetylate the V1E1 subunit of v-ATPase on residues K52, K99 and K191. Muscle-specific expression of a V1E1 mutant (3KR), which mimics the deacetylated state, strongly activates AMPK and rejuvenates muscles in aged mice. In nematodes and flies, LCA depends on the TULP3 homologues tub-1 and ktub, respectively, to activate AMPK and extend lifespan and healthspan. Our study demonstrates that activation of the TULP3-sirtuin-v-ATPase-AMPK pathway by LCA reproduces the benefits of calorie restriction.
    DOI:  https://doi.org/10.1038/s41586-024-08348-2
  12. Circulation. 2024 Dec 14.
    Cardiac Reprogramming and Gata4 Overexpression Reduce Fibrosis and Improve Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.
    Yu Yamada, Taketaro Sadahiro, Koji Nakano, Seiichiro Honda, Yuto Abe, Tatsuya Akiyama, Ryo Fujita, Masashi Nakamura, Takashi Maeda, Yuta Kuze, Masaya Onishi, Masahide Seki, Yutaka Suzuki, Chikara Takeuchi, Yuka W Iwasaki, Kensaku Murano, Mamiko Sakata-Yanagimoto, Shigeru Chiba, Hideyuki Kato, Hiroaki Sakamoto, Yuji Hiramatsu, Masaki Ieda.
       BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major health concern. Pathological stimuli and interactions between cardiac fibroblasts (CFs) and other cell types may lead to cardiac fibrosis and diastolic dysfunction, which are hallmarks of HFpEF. Interstitial and perivascular cardiac fibrosis correlates with poor prognosis in HFpEF; however, mechanisms of fibrosis remain poorly elucidated, and targeted therapies are lacking. Cardiac reprogramming is a promising therapeutic approach for myocardial infarction that facilitates cardiac regeneration and antifibrosis action through Mef2c/Gata4/Tbx5/Hand2 (MGTH) overexpression in resident CFs. However, the efficacy of this approach on HFpEF is yet to be established.
    METHODS: Herein, we examined the effects of cardiac reprogramming in HFpEF using Tcf21iCre/Tomato/MGTH2A transgenic mice, which expressed both MGTH and reporter expression in CFs for cardiac reprogramming and lineage tracing upon tamoxifen administration. To establish HFpEF model mice, we used a combination of a high-fat diet and nitric oxide synthase inhibition. Bulk RNA-sequencing, single-cell RNA-sequencing, and spatial transcriptomics were conducted to determine fibrotic mechanisms and the efficacy of cardiac reprogramming in HFpEF. We generated new tamoxifen-inducible transgenic mice overexpressing each reprogramming factor in CFs to investigate the effect of single factors. Last, we analyzed the effect of reprogramming factors in human CFs.
    RESULTS: Cardiac reprogramming with MGTH overexpression improved diastolic dysfunction, cardiac hypertrophy, fibrosis, inflammation, and capillary loss in HFpEF. Cardiac reprogramming converted approximately 1% of resident CFs into induced cardiomyocytes. Bulk RNA-seq indicated that MGTH overexpression upregulated genes related to heart contraction and suppressed the fetal gene program (Nppa and Nppb) and proinflammatory and fibrotic signatures. Single-cell RNA-sequencing and spatial transcriptomics revealed that multiple CF clusters upregulated fibrotic genes to induce diffuse interstitial fibrosis, whereas distinct CF clusters generated focal perivascular fibrosis in HFpEF. MGTH overexpression reversed these profibrotic changes. Among 4 reprogramming factors, only Gata4 overexpression in CFs reduced fibrosis and improved diastolic dysfunction in HFpEF by suppressing CF activation without generating new induced cardiomyocytes. Gata4 overexpression also suppressed profibrotic signatures in human CFs.
    CONCLUSIONS: Overexpressing Gata4 in CFs may be a promising therapeutic approach for HFpEF by suppressing fibrosis and improving diastolic dysfunction.
    Keywords:  cardiac fibroblasts; fibrosis; heart failure; single-cell RNA-sequencing; spatial transcriptomics
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.067504
  13. Nature. 2024 Dec 18.
    Four-component protein nanocages designed by programmed symmetry breaking.
    Sangmin Lee, Ryan D Kibler, Green Ahn, Yang Hsia, Andrew J Borst, Annika Philomin, Madison A Kennedy, Buwei Huang, Barry Stoddard, David Baker.
      Four, eight or twenty C3 symmetric protein trimers can be arranged with tetrahedral, octahedral or icosahedral point group symmetry to generate closed cage-like structures1,2. Viruses access more complex higher triangulation number icosahedral architectures by breaking perfect point group symmetry3-9, but nature appears not to have explored similar symmetry breaking for tetrahedral or octahedral symmetries. Here we describe a general design strategy for building higher triangulation number architectures starting from regular polyhedra through pseudosymmetrization of trimeric building blocks. Electron microscopy confirms the structures of T = 4 cages with 48 (tetrahedral), 96 (octahedral) and 240 (icosahedral) subunits, each with 4 distinct chains and 6 different protein-protein interfaces, and diameters of 33 nm, 43 nm and 75 nm, respectively. Higher triangulation number viruses possess very sophisticated functionalities; our general route to higher triangulation number nanocages should similarly enable a next generation of multiple antigen-displaying vaccine candidates10,11 and targeted delivery vehicles12,13.
    DOI:  https://doi.org/10.1038/s41586-024-07814-1
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