Microorganisms represent an important component of the tumor microenvironment, but conflicting reports have left the extent of microbial prevalence across cancer types unclear, necessitating more robust methods for chara...Microorganisms represent an important component of the tumor microenvironment, but conflicting reports have left the extent of microbial prevalence across cancer types unclear, necessitating more robust methods for characterizing tumor-associated microbiomes. We built and benchmarked a host-subtraction and classification pipeline to identify microbiota in whole-genome sequencing data and applied it to 16,369 high-depth tumor whole genomes from the UK 100,000 Genomes Project. After decontamination, microbial signatures were indistinguishable from the background in most cancer types. However, in orodigestive tumors, we detected multi-kingdom polymicrobial communities, including bacteria, fungi, viruses, archaea, and, in some cases, Trichomonas, a protozoan parasite. These communities varied by tumor site and subtype, with increased microbial colonization of microsatellite-instable and polymerase ε (POLE)/polymerase δ (POLD1)-mutated tumors, supported by a correlation between microbial load and tumor mutation burden observed across orodigestive cancers. This analysis helps to resolve pan-cancer microbial structure and links the tumor microbiome to host phenotype and tumor genomic context.
Lyu P, Agarwal G, Guo CJ
… +11 more, Sychla A, Bourgeois W, Ye T, Weng C, Antoszewski M, Joubran S, Caulier A, Poeschla M, Armstrong SA, Rouskin S, Sankaran VG
The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with...The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We found that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9, which we named HOXA opposite-strand transcript, stem-cell regulator, antisense mid-cluster between loci (HOTSCRAMBL). The HOTSCRAMBL variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, HOTSCRAMBL enables appropriate expression and splicing of HOXA genes in HSCs, most notably HOXA9, in an SRSF2-dependent manner. Given the critical role of HOXA gene expression in some blood cancers, we also demonstrate that HOTSCRAMBL variation or deletion compromises HOXA-dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression.
Spiga L, Fansler RT, Wu Y
… +25 more, Grote A, Langford-Butler M, Miller AK, Neal M, Hale OF, Singla D, Calcutt MW, Rose AE, Bresson MM, Schrimpe-Rutledge AC, Berdy B, Codreanu SG, Washington MK, Bratton BP, Sherrod SD, McLean JA, Zengler K, Sears CL, Behringer MG, Gnirke A, Tao L, Livny J, Olivares-Villagómez D, Earl AM, Zhu W
To colonize their host and cause disease, enteric pathogens must deploy their virulence factors to establish distinct nutrient niches. How anaerobic pathogens construct nutrient niches in the densely populated large inte...To colonize their host and cause disease, enteric pathogens must deploy their virulence factors to establish distinct nutrient niches. How anaerobic pathogens construct nutrient niches in the densely populated large intestine remains poorly understood. Enterotoxigenic Bacteroides fragilis (ETBF) is a classically anaerobic bacterium implicated in inflammation-associated diseases, including colitis and colorectal cancer. Here, we show that ETBF uses its virulence factor, Bacteroides fragilis toxin (BFT), to generate and adapt to a localized oxidative niche that supports gut colonization. BFT manipulates colonic epithelial signaling and the bile acid recycling pathway, inducing a metabolic shift in the epithelium from oxidative phosphorylation to glycolysis. This shift increases local concentrations of lactate and oxygen, nutrients that support oxidative metabolism in ETBF. These findings reveal an unexpected strategy by which a classically anaerobic pathogen leverages host metabolic remodeling to generate and exploit an oxidative niche in the inflamed gut.
Gattinoni L, Inchingolo G, Harrer DC
… +28 more, Susana A, Puccio S, Slavkovic-Lukic D, Natrakul DA, Strieder N, Heuser-Loy C, Baldwin JG, Fioravanti J, Ji Y, Gautam S, Suriano C, Martín-Santos A, Schelker RC, Patel N, Mann J, Goff S, Mikkilineni L, Yang JC, Kwong MLM, Patel R, Rehli M, Highfill SL, Stroncek DF, Rosenberg SA, Biasco L, Lugli E, Brudno JN, Kochenderfer JN
Donor-derived CD19-CAR T cells offer a therapeutic option for B cell malignancies relapsing after allogeneic hematopoietic stem cell transplantation but are often constrained by poor engraftment, expansion, and persisten...Donor-derived CD19-CAR T cells offer a therapeutic option for B cell malignancies relapsing after allogeneic hematopoietic stem cell transplantation but are often constrained by poor engraftment, expansion, and persistence. In a first-in-human study (NCT01087294), we found that CAR-modified stem-cell memory T (T) cells exhibited greater expansion and persistence than standard CAR T cells, enabling complete responses at low doses in the absence of lymphodepletion. CAR T cells induced mild cytokine-release syndrome, dominated by IFN-γ. Both products differentiated into effectors; however, only CAR T cells robustly reconstituted the stem-like compartment over time. CAR T cells were sustained through clonal succession, whereas persisting standard CAR T cells resulted from maintenance or contraction of early-expanded clones. While poor expansion limited standard CAR T cell activity, resistance to CAR T cells was driven primarily by tumor- and host-related factors. These findings establish CAR T cells as a promising platform for next-generation CAR T cell therapies.
Wang L, Amar M, Arbizu CI
… +52 more, Bowman JL, Cannon CH, Cantrill DJ, Cao X, Chen S, Chen X, Chen X, Chong K, Deng X, Weinan E, Guo H, He C, Hollingsworth P, Hu Q, Kong H, Leitch IJ, Li D, Li J, Liu H, Lucas W, Mizrachi E, Rakotoarinivo M, Ren H, Rieseberg L, Ruan J, Scherson R, Schneider H, Soltis DE, Sun H, Silva-Filho MC, Smith S, Twyford A, Usadel B, Van de Peer Y, Van den Berg C, Varshney RK, Viccini LF, Wang Q, Wang XQ, Wang Y, Wendel J, Wing R, Wong GK, Xing Y, Xu X, Yan N, Yang H, Zhang S, Zhu Y, Soltis PS, Weigel D, Huang S
Land plants underpin civilization and planetary health, yet their genomic diversity remains largely uncharted. Current resources are unstandardized and scarce, lacking reference genomes for 95% of genera, 70% of families...Land plants underpin civilization and planetary health, yet their genomic diversity remains largely uncharted. Current resources are unstandardized and scarce, lacking reference genomes for 95% of genera, 70% of families, and 51% of orders, impeding evolutionary and functional insight. We thus propose the PLANeT initiative, an international effort to generate high-quality, standardized genomes across the plant tree of life. Integrating artificial intelligence (AI) with genomics, we will decode conserved principles to advance fundamental plant biology, biodiversity conservation, crop improvement, and natural product discovery. Engaging around 100 labs to train 1,000 scientists, we will tackle pivotal questions for a sustainable future.
Hu et al identify ROCK2 in liver sinusoidal endothelial cells as a key factor in liver fibrosis. Through single-cell analysis, knockout models, protein studies, and early clinical research, the authors show that ROCK2-dr...Hu et al identify ROCK2 in liver sinusoidal endothelial cells as a key factor in liver fibrosis. Through single-cell analysis, knockout models, protein studies, and early clinical research, the authors show that ROCK2-driven endothelial cytoskeletal changes trigger angiocrine signals that activate hepatic stellate cells-highlighting a potential therapeutic target.
Scharping NE, Ge X, Matias MI
… +17 more, Jiang F, Cafferata A, Heeg M, Monell A, Galletti G, Cheung KP, Rock A, Thao N, Shuttleworth SL, Bauer MA, Takehara KK, Ferry A, Quon S, Koss B, Myers SA, Bennett EJ, Goldrath AW
Tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to progressive differentiation into an "exhausted" state. Tissue-resident memory T cells (T) maintain protection from infection for years in he...Tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to progressive differentiation into an "exhausted" state. Tissue-resident memory T cells (T) maintain protection from infection for years in healthy tissues, and patient tumors that contain TIL with T features are associated with better prognosis. Proteomic and transcriptomic profiling of T cell populations identified proteostasis as a significant factor distinguishing T and progenitor-exhausted TIL from terminally exhausted TIL, including loss of E3 ubiquitin ligases NEURL3, RNF149, and WSB1, with accumulation of unfolded proteins despite functional proteasome activity. Enforced expression of these ligases in T cells preserved stem-like TCF1 populations and improved function in tumors and chronic infection, whereas deficiency impaired TIL and altered T cell differentiation during acute infection. Sustained ligase expression rescued the accumulation of unfolded proteins in TIL and improved immunotherapy outcomes in preclinical models, underscoring the critical role of proteostasis in TIL function and highlighting a promising avenue for advancing cancer immunotherapy.
Xue L, Gui J, Gao S
… +17 more, Gao X, Chang T, Pan H, Tang J, Zhang M, Li Z, Zou B, Zhao H, Wang L, Li M, Rong L, Plemper RK, Chen X, He J, Pei R, Zhan P, Xiong X
ERDRP-0519 is a non-nucleoside polymerase inhibitor developed against measles virus (MeV) of the Morbillivirus genus. Here, we show that ERDRP-0519 also cross-inhibits Nipah virus (NiV) of the Henipavirus genus with redu...ERDRP-0519 is a non-nucleoside polymerase inhibitor developed against measles virus (MeV) of the Morbillivirus genus. Here, we show that ERDRP-0519 also cross-inhibits Nipah virus (NiV) of the Henipavirus genus with reduced potency. ERDRP-0519 binds to a shared pocket within the RNA-dependent RNA polymerase (RdRp) palm domains of MeV, peste des petits ruminants virus (PPRV), and NiV polymerases. ERDRP-0519 forms more extensive interactions with Morbillivirus polymerases, whereas binding to NiV polymerase requires substantial RdRp motif rearrangements, likely incurring an energetic cost and resulting in reduced affinity. ERDRP-0519 binding impedes RNA synthesis by sterically blocking RNA and nucleotide binding. Guided by these insights, we designed GL22 and G671, ERDRP-0519 derivatives with extended moieties that engage additional cross-domain RdRp contacts in the NiV polymerase. These derivatives exert more extensive steric hindrance to RNA and nucleotide binding, enhancing biochemical inhibition potency. These findings elucidate the molecular mechanism of ERDRP-0519 action and guide structure-based inhibitor design.
The detection of olfactory cues is essential to signal food, predators, and social encounters. To determine how the sensory detection of physiologically relevant odors is systematically mapped into the mouse primary olfa...The detection of olfactory cues is essential to signal food, predators, and social encounters. To determine how the sensory detection of physiologically relevant odors is systematically mapped into the mouse primary olfactory system, we used multiplexed error-robust fluorescent in situ hybridization (MERFISH) to construct a molecular atlas of olfactory receptor (OR) expression in the main olfactory epithelium (MOE) and olfactory bulb (OB). We comprehensively quantified the expression of the mouse OR repertoire and uncovered stereotypical gradients of sensory neuron distribution in the MOE along two axes, central-to-peripheral and apical-to-basal. Projections of sensory neurons mirror these two MOE gradients along the dorsal-ventral and anterior-posterior axes of the OB, respectively. Integration with sequencing data revealed candidate signaling molecules underlying this spatial organization. Co-imaging OR and activity marker expression identified distinct spatial domains of sensory responses in the MOE and OB, providing a topographical basis for olfactory responses to ethologically relevant odors.
Xu Z, Liu F, Ding Y
… +27 more, Pan T, Wu YH, Han Y, Liu J, Bado IL, Zhang W, Wu L, Gao Y, Hao X, Yu L, Li X, Edwards DG, Chan HL, Aguirre S, Dieffenbach MW, Chen E, Wang S, Shen Y, Hoffman D, Becerra Dominguez L, Rivas CH, Chen X, Wang H, Kang Y, Gugala Z, Satcher RL, Zhang XH
Metastatic cancer cell fate is shaped by the local microenvironment niches. To unbiasedly define the cellular and molecular features of metastatic niches, we developed sortase A-based microenvironment niche tagging (SAME...Metastatic cancer cell fate is shaped by the local microenvironment niches. To unbiasedly define the cellular and molecular features of metastatic niches, we developed sortase A-based microenvironment niche tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastasis. Applying SAMENT across multiple cancer models and target organs revealed shared niche features, including macrophage enrichment and T cell depletion, alongside marked organ-specific phenotype heterogeneity in niche macrophages. In bone, metastatic niches are enriched for macrophages expressing estrogen receptor alpha (ERα) with active ERα signaling. Conditional deletion of Esr1 in macrophages significantly impaired bone colonization by enabling T cell infiltration. ERα⁺ macrophages were also identified in human bone metastases across multiple cancer types. Together, these findings define a distinct ERα⁺ macrophage niche and establish macrophage ERα signaling as a key driver of T cell exclusion during metastatic colonization.
Endoplasmic reticulum (ER) redox homeostasis is critical for ER functionality and is implicated in various human diseases, yet its physiological significance in plants remains largely elusive. Ethylene, a key phytohormon...Endoplasmic reticulum (ER) redox homeostasis is critical for ER functionality and is implicated in various human diseases, yet its physiological significance in plants remains largely elusive. Ethylene, a key phytohormone, is perceived and transduced at the ER, suggesting an underexplored connection between the ER and ethylene signaling. Here, we show that ethylene receptors sense the ER redox state via lumen-localized intermolecular disulfide bonds. ER reductive stress, rather than ethylene, disrupts the disulfide-linked dimers of the receptors, repressing their function and thereby activating downstream ethylene signaling. Moreover, modulating disulfide bond formation in the receptor ETHYLENE RESPONSE 1 (ETR1) through ER redox shifts supports plant resilience under hypoxia and during photomorphogenesis. Finally, our findings suggest that sensing ER redox may be an ancestral receptor function, predating the substantial emergence of ethylene biosynthesis. This study illuminates a deeper nexus between organelle homeostasis and hormone signaling.
Dimerization is crucial for the activation of ErbB family receptors, yet the real-time dynamics and effects of oncogenic mutations remain unclear. Here, we performed long-term, multicolor single-particle tracking (SPT) o...Dimerization is crucial for the activation of ErbB family receptors, yet the real-time dynamics and effects of oncogenic mutations remain unclear. Here, we performed long-term, multicolor single-particle tracking (SPT) of EGFR, HER2, and HER3 in living cells using upconverting nanoparticles (UCNPs), which do not photobleach. Our technique enables continuous observation of receptor interactions, revealing details of their dimerization dynamics. Oncogenic EGFR mutations promote stable, ligand-independent dimerization. Unexpectedly, both HER2 and HER3 exhibit constitutive homodimerization, prompting a revised model for their activation mechanisms. HER2 mutations modestly enhance homodimer stability compared with EGFR mutations, while HER3 mutations destabilize homodimers, suggesting that HER3 homodimerization sequesters HER3 and limits heterodimerization with other receptors. We also identified stable, ligand-independent heterodimers among all three receptors, further stabilized by ligand stimulation. These insights offer a comprehensive ErbB interaction network, elucidating diverse dimerization mechanisms and implications for oncogenic signaling.
Brann DH, Tsukahara T, Tau C
… +11 more, Kalloor D, Lubash R, Kannan LT, Klimpert N, Kollo M, Escamilla-Del-Arenal M, Bintu B, Schaefer A, Fleischmann A, Bozza T, Datta SR
Although topographical maps organize many peripheral sensory systems, mouse olfactory sensory neurons (OSNs) are thought to randomly choose which one of ∼1,100 possible olfactory receptors (ORs) to express, with spatial...Although topographical maps organize many peripheral sensory systems, mouse olfactory sensory neurons (OSNs) are thought to randomly choose which one of ∼1,100 possible olfactory receptors (ORs) to express, with spatial organization in the olfactory epithelium limited to a handful of broad anatomical "zones" that modestly restrict OR choice. Here, we reveal that each OR is instead expressed at a unique mean dorsoventral position, thereby instantiating a stereotyped receptor map in the olfactory epithelium. OSN dorsoventral identities are encoded by a coherent gene expression program, which includes key transcription factors and axon guidance molecules; use of this program reflects a dorsoventral gradient in retinoic acid signaling, translates each physical location into a spatially appropriate distribution of potential OR choices, and aligns receptor maps in the nose and brain. Spatial order in the olfactory system, therefore, arises from a continuously varying transcriptional code that precisely organizes the many discrete channels responsible for smell.
Billmann M, Costanzo M, Zhang X
… +87 more, Hassan AZ, Rahman M, Brown KR, Chan KS, Tong AHY, Pons C, Ward HN, Ross C, van Leeuwen J, Aregger M, Lawson KA, Mair B, Roth AF, Sen NE, Forster DT, Tan G, Mero P, Masud SN, Lee Y, Aguilera-Uribe M, Ušaj M, Almeida SMT, Aulakh K, Bhojoo U, Birkadze S, Budijono N, Cai X, Caumanns JJ, Chalmers JJ, Chandrashekhar M, Chang D, Climie R, Dasgupta K, Drazic A, Echenique JIR, Gacesa R, Farias AG, Habsid A, Horecka I, Kantautas K, Ji F, Kim DK, Lee SY, Liang W, Lim HJ, Lin K, Lu X, Maier M, Nami B, Nixon A, Mikolajewicz N, Mokhtaridoost M, Nedyalkova L, Rohde T, Rodrigues MS, Soste M, Schultz E, Wang W, Seetharaman A, Shuteriqi E, Sizova O, Taylor DT, Tereshchenko M, Tieu D, Turowec J, Ubhi T, Varland S, Wang KE, Wang ZY, Wei J, Xiao YX, Maass PG, Reversade B, Brown GW, Cravatt BF, Dixon SJ, Wyatt HDM, Röst HL, Roth FP, Xia T, Bader GD, Loewith R, Davis NG, Andrews B, Myers CL, Moffat J, Boone C
Deciphering how genes interact within human cells is essential for understanding their functional wiring and for developing targeted therapeutic strategies. In this study, we present a genome-scale map of genetic interac...Deciphering how genes interact within human cells is essential for understanding their functional wiring and for developing targeted therapeutic strategies. In this study, we present a genome-scale map of genetic interactions in the human haploid cell line HAP1, based on CRISPR-based perturbation of ∼4 million gene pairs. The resulting network comprises ∼89,000 high-confidence gene-gene interactions, organizing genes into hierarchical modules corresponding to protein complexes and pathways, biological processes, and cellular compartments, mirroring principles observed in yeast and highlighting the functional architecture of a human cell. This large-scale genetic network complements the DepMap gene co-essentiality network by capturing unique functional information, uncovering roles of previously uncharacterized genes, and identifying molecular determinants of cancer-cell-line-specific genetic dependencies. This study presents a general data-driven strategy for systematically exploring the roles of genes and their functional connections in human cell lines.
Ferroptosis is an iron-dependent form of regulated cell death. However, the critical regulators that restrain iron overload to suppress ferroptosis remain undefined. Utilizing multi-omics, we identify the E3 ubiquitin li...Ferroptosis is an iron-dependent form of regulated cell death. However, the critical regulators that restrain iron overload to suppress ferroptosis remain undefined. Utilizing multi-omics, we identify the E3 ubiquitin ligase membrane-associated RING-CH 7 (MARCH7) as a non-redundant, dual suppressor of ferroptosis via direct regulation of intracellular iron homeostasis. Mechanistically, MARCH7 ubiquitylates nuclear receptor coactivator 4 (NCOA4) at residue Lys42 by K48-linked ubiquitination, promoting NCOA4 proteasomal degradation and reducing the labile iron pool. Concomitantly, MARCH7 modifies transferrin receptor 1 (TFR1) at residue Lys53 by K63 ubiquitination, restricting its plasma membrane translocation and thereby inhibiting cellular iron uptake. Through high-content screening, we further identify emodinanthrone (EmodAn) as a specific MARCH7 stabilizer with a strong cardioprotective effect in rodent models by blocking ferroptosis. In conclusion, our findings define an iron homeostasis regulatory hub for ferroptosis and suggest that stabilizing MARCH7 is a promising therapeutic strategy to protect against ferroptosis- or iron-overload-induced diseases.
Aggarwal N, Shen H, Lee LT
… +17 more, Zhou L, Zhu MT, Koh XQ, Ng AXY, Li M, Jumat NHB, Cheah WY, Li S, Saini M, Lee JWJ, Foo JL, Wun KS, Hwang IY, Ho CL, Lee YS, Dan YY, Chang MW
The gut-liver-brain axis is central to metabolic and neurological homeostasis and is mediated by host- and microbiota-derived metabolites. Disruptions in this axis contribute to complex disorders, underscoring the need f...The gut-liver-brain axis is central to metabolic and neurological homeostasis and is mediated by host- and microbiota-derived metabolites. Disruptions in this axis contribute to complex disorders, underscoring the need for targeted, multi-metabolite interventions. Here, we engineered commensal Lactobacillus plantarum WCFS1 strains to specifically modulate metabolites dysregulated in hepatic encephalopathy (HE), a disorder driven by hyperammonemia and amino acid imbalance. One strain couples ammonia assimilation with branched-chain amino acid (BCAA) biosynthesis, whereas the other enhances L-glutamine utilization to suppress ammonia generation. In two preclinical HE models, these strains reduced systemic ammonia by up to 10-fold, restored BCAA and L-glutamine balance, and improved anxiety-like and cognitive behaviors. Notably, they outperformed rifaximin, a clinically used HE therapy, while preserving gut microbiota diversity. These findings establish engineered commensals as a modular, responsive platform for multi-metabolite modulation of host-microbiota metabolism, offering a programmable strategy to restore metabolic homeostasis in disorders of the gut-liver-brain axis.
Nuclear envelope (NE) budding (NEB) has emerged as an alternative route for nuclear export of viral particles that are too large to pass through the nuclear pore complex. Yet the significance of this unconventional expor...Nuclear envelope (NE) budding (NEB) has emerged as an alternative route for nuclear export of viral particles that are too large to pass through the nuclear pore complex. Yet the significance of this unconventional export pathway for large endogenous cargoes in mammalian cells has remained largely unexplored. Here, we use a combination of electron and fluorescence microscopy to demonstrate that NEB events occur following myoblast differentiation into myotubes and concomitant with the expression of extremely long muscle-specific transcripts. We show that NE buds are derived from the inner nuclear membrane, contain internal vesicles, and are specifically enriched with long sarcomeric transcripts. We identify a role for the protein UAP56-interacting factor (UIF) in regulating mRNA cargo targeting into NE buds and show that this pathway requires the endosomal sorting complex required transport III (ESCRT-III) membrane remodeling machinery. Our findings uncover a non-canonical pathway for large transcript nuclear export in muscle cells and provide insight into its mechanism.
Munguba H, Arefin A, Hasegawa R
… +17 more, Posa L, Romano GR, Peddada TN, Donatelle A, Singh A, Gutzeit VA, Vijay A, Vaddi P, Kristt M, Shaver D, Hoque S, Broichhagen J, Stujenske JM, Lee FS, O'Brien E, Levitz J, Liston C
Depression is driven by dysfunction in discrete neural circuits, but a deeper understanding of the underlying molecular and synaptic mechanisms is needed to guide the development of therapeutics. Here, we decipher the me...Depression is driven by dysfunction in discrete neural circuits, but a deeper understanding of the underlying molecular and synaptic mechanisms is needed to guide the development of therapeutics. Here, we decipher the mechanisms of action of the fast-acting antidepressant ketamine to enable the identification of G protein-coupled receptor (GPCR) antidepressant targets. We find that the behavioral effects of ketamine rely on mu-opioid receptors (MORs), which are enriched in somatostatin-expressing interneurons (Sst INs) in the medial prefrontal cortex (mPFC). Chronic stress drives presynaptic hypertrophy of mPFC Sst INs and excessive inhibition of pyramidal neurons, which is rescued by ketamine. Motivated by these findings, we use RNA sequencing to identify mPFC Sst IN-enriched GPCRs and validate the antidepressant potential of promising targets. Synergistic targeting of multiple GPCRs enables potent antidepressant-like responses with reduced side effects. Together, these findings reveal a general approach to identifying therapeutic GPCR targets for brain disorders.
Spatial genome organization plays a crucial regulatory role, but its evolutionary development remains unclear. Leveraging Hi-C data from 1,025 species, we trace the evolutionary trajectories of genome organization throug...Spatial genome organization plays a crucial regulatory role, but its evolutionary development remains unclear. Leveraging Hi-C data from 1,025 species, we trace the evolutionary trajectories of genome organization through 2 higher-order architectures, "global folding" (spatial organization of the karyotype) and "checkerboard" (spatial organization of chromatin compartments). Earlier unicellular life forms mostly displayed random genome configurations. Throughout the evolution of plants, global folding became and remained the prominent architecture. However, animals progressively developed more pronounced checkerboard architectures; these are also apparent during early embryogenesis, which suggests that they act as a conserved mechanism of gene regulation. In contrast, plants exhibit comparatively weaker checkerboard patterns and instead preferentially organize co-regulated genes into linear genomic clusters. Both strategies of gene arrangement reinforce the biological principle that "structure determines function": divergent evolutionary paths converge on architectural solutions that reflect gene regulatory requirements over time.