Biology subjects

Liu, M.

Publications and source records attributed to Liu, M..

At least 181 records · Page 10Linked to original sources

bioRxiv2024

Characterizing Tyrosine Ring Flips in Proteins by 19F NMR

Aromatic ring-flip dynamics are hallmarks of concerted protein "breathing" motions that are essential for biological function. Ring flips occur on a broad range of timescales (ns-s) and have been primarily studied by NMR spectroscopy, typically requiring expensive isotope labeling of aromatic side chains, thereby limiting such studies to a few proteins. Here, we report two novel di-fluorotyrosine probes, 3,5-F2Y and 2,6-F2Y, that can be incorporated into proteins cost-effectively for characterizing and modulating tyrosine ring-flip dynamics. We show that 19F rotating-frame (R1{rho}) relaxation dispersion is powerful for quantifying ring flips on the {micro}s-ms timescale. Importantly, the tyrosine ring-flip rates (kflip) for 3,5-F2Y in GB1 and HPr are comparable to those measured by 1H and 13C NMR studies, validating 3,5-F2Y as a largely non-perturbing, native-like ring-flip probe. In contrast, 2,6-F2Y acts as an effective "brake" on ring flips, enabling direct visualization and quantitative characterization of previously undetected tyrosine ring flips in ubiquitin via 19F lineshape analysis. Furthermore, we use 2,6-F2Y to assess the environmental effects on ring-flip dynamics in crowding reagents and in living X. laevis oocytes. Collectively, our study opens a new avenue for measuring and modulating ring-flip dynamics in vitro and in living cells. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/630691v2_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@dcf8e1org.highwire.dtl.DTLVardef@1578887org.highwire.dtl.DTLVardef@1c481d0org.highwire.dtl.DTLVardef@268ae0_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Lysosomal reduced thiols are essential for mouse embryonic development

While it has been appreciated for decades that lysosomes can import cysteine, its for organismal physiology is unclear. Recently, the MFSD12 transmembrane protein was shown to be necessary to import cysteine into lysosomes (and melanosomes), enabling the study of these processes using genetic tools. Here, we find that mice lacking Mfsd12 die between embryonic days 10.5-12.5, suggesting that MFSD12 is essential for organogenesis. Within lysosomes, it is well known that a significant fraction of the cysteine is converted into cystine (oxidized cysteine), which accumulates and can be released into the cytosol via the CTNS (cystinosin) transporter. However, in contrast to Mfsd12, loss of Ctns results in live animals, indicating that it is not an essential gene. This suggests that the essential function of MFSD12 is not to enable cystine storage for use in the cytosol but rather to supply reduced cysteine to the lysosomal lumen itself. Consistent with this idea, the treatment of breeding heterozygous mice with cysteamine, a lysosome-penetrant thiol, rescued the development of Mfsd12 knockout mice and resulted in live births. Our work implicates lysosomal thiol import as an essential metabolic pathway and provides tools for deciphering its complex genetic and metabolic interactions.

cell biology↗

bioRxiv2024

The structural basis for de novo DNA methylation in chromatin

De novo cytosine methylation is essential for mammalian development and is deposited by DNMT3A and DNMT3B. In cells, DNA methylation occurs in the context of chromatin, where nucleosomes are connected by DNA linkers. Here, we report Cryo-EM structures of DNMT3A2/3B3 bound to di-nucleosomes with different linker lengths. We show that DNMT3A2/3B3 preferentially binds di-nucleosomes separated by short DNA linkers by inducing large-scale changes to the di-nucleosome structure, enabling each DNMT3B3 subunit to bind each nucleosome. Linker length and the position of cytosines within the linker control DNA methylation, indicating that a significant fraction of linkers in chromatin are naturally resistant to DNMT3A2/3B3 activity. Finally, DNMT3A2/3B3 scans for H3K36me2-3 modifications, explaining how H3K36 methylation simulates DNMT3A2 activity. Our structure is the first example of a DNA methyltransferase interacting with higher-order nucleosome substrates and provides new insights on how DNA methylation takes place in chromatin.

biophysics↗

bioRxiv2024

Mechanism of D-type cyclins recognition by the AMBRA1 E3 ligase receptor

AMBRA1 is a tumour suppressor protein that functions as a substrate receptor in the ubiquitin conjugation system and regulates the stability of D-type cyclins and cell proliferation. Here, we present the cryo-EM structure of cyclin D1 bound AMBRA1-DDB1 complex at 3.5 [A] resolution. The structure reveals a substrate interaction surface on the AMBRA1 WD40 domain that specifically binds to the C-terminal region of D-type cyclins. This interaction is dependent on the phosphorylation of Thr286 residue in the C-terminal phosphodegron site of D-type cyclins. The phosphodegron motif folds into a turn-like conformation followed by a 310 helix that promotes its assembly with AMBRA1. Additionally, we show that AMBRA1 mutants, which are defective in cyclin D1 binding, lead to cyclin D1 accumulation and DNA damage. Understanding the AMBRA1-D-type cyclins structure enhances the knowledge of the molecular mechanisms that govern the cell cycle control and may lead to new therapeutic approaches for cancers linked to abnormal cyclin D activity.

biochemistry↗

bioRxiv2024

Epigenetic reprogramming induced by Acetyl-CoA and SAM depletion is an evolutionarily-ancient path to malignant growth

Despite the vast diversity of life forms and living histories, it appears that all branches of Metazoa face the challenge of tumor growth. Contrary to human tumors, which take years to form, tumors in short-living species can arise within days without accumulating multiple mutations, raising the question whether the paths to tumorigenesis in diverse species have any commonalities. In a fly tumor model caused by loss of cell polarity genes, we first identified the rise of a glycolytic cell population over time, resembling the Wartburg effect observed in human tumors. We further identified two key metabolic changes in these fly tumors. First, a systemic depletion of acetyl-CoA leads to a reduction in histone acetylation levels and stochastic silencing of actively-transcribed genes. Second, defects in the methionine cycle cause a systemic depletion of S-Adenosyl methionine, which further reduces histone methylation levels and causes stochastic activation of transposons. Perturbation of the methionine metabolic process strongly inhibits tumor growth. Finally, to understand the evolutionary origin of tumorigenesis, we performed comparative studies of fly and human tumors, and identified human tumors that exhibit metabolic signatures similar to those of fly tumors. We found that human tumors with high metabolic similarity to fly tumors have a lower mutational load, younger patient age, and lower DNA methylation levels. This study suggests that tumorigenesis processes have a deep evolutionary origin and highlights that depletion of key metabolites is an evolutionarily-ancient driving force for tumorigenesis.

developmental biology↗

bioRxiv2024

STING agonists drive recruitment and intrinsic type I interferon responses in monocytic lineage cells for optimal anti-tumor immunity

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a sensor of cytosolic DNA, orchestrates the production of pro-inflammatory cytokines, chemokines, and type I interferons (IFN-I), thereby contributing to spontaneous tumor surveillance. Intratumoral delivery of synthetic STING agonists induces IFN-I dependent tumor regression in preclinical cancer models and is being tested clinically. In this study, we investigate the role of monocytic lineage (MCs) cells in response to STING agonist induced IFN-I signaling. We show that CCR2-deficient mice, lacking inflammatory MCs in the periphery, or Lyz2-Cre-IFNAR1fl/fl mice in which IFN-I signaling in monocytes is reduced, exhibit impaired responses to STING agonist therapy of MC38 and/or B16F10 tumors. STING agonist treatment induced CCR5-dependent migration of MCs carrying tumor antigen from the tumor to the lymph nodes. Single-cell RNA sequencing of CD45+ cells from lymph nodes and tumors of mice in which half the hematopoietic cells lack the interferon alpha/beta receptor 1 (IFNAR1) revealed that STING agonist therapy induces intrinsic IFNAR1-dependent acquisition of an inflammatory monocytic cell phenotype distinct from inflammatory cDC and a reduction in macrophages with a pro-tumor TGF{beta}/angiogenesis transcriptome. IL-18 - IL-18R1 interaction was the top predicted interaction between monocytic lineage cells and CD8+T cells or NK cells. Blocking IL-18 reduced IFN-{gamma} production by CD8 T cells in LNs and decreased the therapeutic efficacy of STING agonist treatment in CCR2+/+ but not in CCR2-/- mice. These findings support a pivotal role for IL-18 producing inflammatory monocytic lineage cells in CD8 T cell control of melanoma following STING agonist treatment.

immunology↗

bioRxiv2024

Ubiquitin Ligase ITCH Regulates Life Cycle of SARS-CoV-2 Virus

SARS-CoV-2 infection poses a major threat to public health, and understanding the mechanism of viral replication and virion release would help identify therapeutic targets and effective drugs for combating the virus. Herein, we identified E3 ubiquitin-protein ligase Itchy homolog (ITCH) as a central regulator of SARS-CoV-2 at multiple steps and processes. ITCH enhances the ubiquitination of viral envelope and membrane proteins and mutual interactions of structural proteins, thereby aiding in virion assembly. ITCH-mediated ubiquitination also enhances the interaction of viral proteins to the autophagosome receptor p62, promoting their autophagosome-dependent secretion. Additionally, ITCH disrupts the trafficking of the protease furin and the maturation of cathepsin L, thereby suppressing their activities in cleaving and destabilizing the viral spike protein. Furthermore, ITCH exhibits robust activation during the SARS-CoV-2 replication stage, and SARS-CoV-2 replication is significantly decreased by genetic or pharmacological inhibition of ITCH. These findings provide new insights into the mechanisms of the SARS-CoV-2 life cycle and identify a potential target for developing treatments for the virus-related diseases.

molecular biology↗

bioRxiv2024

Dynamic interplay between RNA N6-methyladenosine modification and porcine reproductive and respiratory syndrome virus infection

N6-methyladenosine (m6A) has attracted significant attention for its role in various biological processes, including RNA stability, translation, and the immune response. Understanding the role of m6A in viral infections is crucial to deep the complex interaction between virus and host cells. Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is a significant pathogen affecting swine health worldwide. Here, we firstly identified the m6A peaks in the PRRSV genome by m6A RNA immunoprecipitation sequencing (m6A-seq). Seven m6A-enriched regions within the PRRSV genome were detected, with one located in the N protein-coding region and the others distributed across nonstructural protein-coding regions. Notably, the Nsp2-coding region contained the highest m6A peak, spanning approximately 178 nucleotides. Functional analyses demonstrated a positive correlation between m6A modification levels and PRRSV replication in porcine alveolar macrophages (PAMs), as modulating the expression of m6A methyltransferases and demethylases significantly influenced viral replication. Moreover, treatment with the universal methylation inhibitor 3-deazaadenosine (3-DAA) effectively suppressed PRRSV replication, suggesting its potential as a novel anti-PRRSV therapeutic. To further elucidate the role of m6A in PRRSV infection, we analyzed the m6A landscape in PAMs infected with pandemic and highly pathogenic PRRSV strains. Among the 4,677 transcripts exhibiting altered m6A modification levels, the MAPK14 gene as well as other genes in p38/MAPK signaling pathway potentially emerged as the preliminary targets of m6A-mediated epigenetic regulation during PRRSV infection. These findings provide new insights into the epigenetic mechanisms underlying PRRSV infection and may facilitate the development of targeted anti-PRRSV strategies and therapeutics. IMPORTANCEThe involvement of m6A in viral genome has broader implications for our understanding of virus evolution and pathogenicity. The ability of viruses to adapt to their hosts and exploit host cellular mechanisms is a critical factor in their success as pathogens. As m6A is a modification that can be manipulated by both host and virus, studying its role in viral infections may reveal new insights into viral evolution. Understanding how different viruses utilize m6A could inform strategies for developing antiviral therapies that target these interactions. Such therapies could disrupt the ability of viruses to exploit m6A modifications, potentially reducing their virulence and enhancing host defenses.

microbiology↗

bioRxiv2024

Mapping the endosomal proximity proteome reveals Retromer as a hub for RAB GTPase regulation.

Endosomal retrieval and recycling of integral cargo proteins is essential for cell, tissue and organism-level development and homeostasis and is orchestrated through a specialised retrieval sub-domain on the endosomal vacuole. However, although sub-domain dysfunction is associated with human disease our appreciation of the molecular details and functional components of the retrieval sub-domain(s) remains poorly described. Here, using comparative proximity proteomics of critical retrieval sub-domain components Retromer and Retriever, their cargo adaptors, and a component of the opposing ESCRT-degradative sub-domain, we provide a data-rich resource that identifies new molecular details of retrieval sub-domain composition and organization, including an unrecognised complexity in the interface of Retromer with RAB GTPases. Combining X-ray crystallography and in silico predictions with extensive biochemical and cellular analysis, we dissect the direct association of Retromer with RAB10 regulators DENND4A, DENND4C, TBC1D1, and TBC1D4, and the RAB35 regulator TBC1D13. Overall, we conclude that the Retromer retrieval sub-domain constitutes a major hub for the regulated switching of selected RAB GTPases and propose that this constitutes a major component of the role of Retromer in neuroprotection.

cell biology↗

bioRxiv2024

Engineered mitochondrial A-to-G editors with enhanced efficiency and targeting scope

Mitochondrial base editing is a powerful technology, but the current A-to-G mitochondrial DNA (mtDNA) base editors are reluctant to achieve high efficiency, which is critical for mtDNA engineering. Through laboratory evolution, TadA-8e variants were discovered with substantially increased activity and expanded targeting compatibility, especially for previously unfavorite sequence contexts, when applied to both nuclear and mitochondrial ABEs. Further engineering of the mtDNA editors (eTd-mtABEs) dramatically reduced both DNA and RNA off-targeting effects and enhanced strand-selective A-to-G editing with substitution of DddA to DNA nickases. Moreover, the eTd-mtABEs induced up to 145-fold editing frequencies compared to previous mtDNA adenine base editors in rat cells, and installed targeted mutations in all injected rat embryos with up to 74% efficiency in founders, resulting generation of SNHL and Leigh syndrome models with severe defects. It suggests that eTd-mtABEs are promising mtDNA engineering technology for basic research and for translational studies. HighlightsO_LIEngineered TadA variants enhance nuclear and mitochondrial ABE activity in all sequence contexts. C_LIO_LIAdditional mutations in eTd-mtABEs further minimize both DNA and RNA off-targeting effects. C_LIO_LIEngineered TadA variants are compatible to DNA nickase assisted strand-selective mtDNA editing. C_LIO_LIeTd-mtABEs enable highly efficient generation of rat mtDNA disease models with severe phenotypes. C_LI

bioengineering↗

bioRxiv2024

Classifying Irritable Bowel Syndrome Using Spatio-Temporal Graph Convolution Networks on Brain fMRI Data

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder marked by abdominal pain and changes in stool consistency or frequency. Recent studies have explored the link between IBS and various cognitive deficits using functional MRI. Despite these efforts, an effective diagnostic or predictive model for IBS remains elusive. This shortfall is twofold: firstly, the sample sizes in these studies are typically small, and secondly, the machine learning or deep learning models currently in use fail to adequately detect the subtle and dynamic pathological changes present in fMRI data for IBS. In this study, we extracted rs-fMRI of 79 subjects with IBS and 79 healthy controls, then put them into spatio-temporal graph convolution network (ST-GCN) for classification. We also incorporated a novel interpretability module into this model to identify potential regions of interest (ROI) associated with IBS. Our model outperformed other state-of-the-art ML and DL methods with the highest average accuracy of 83.51% on our dataset. Furthermore, based on the results of our interpretability module, the Inferior Parietal Lobule (IPL.R), Inferior Frontal Orbital part (ORBinf.R), Postcentral Gyrus (PCG.R), Middle Frontal Orbital part (ORBmid.R), and Superior Medial Frontal Orbital part (ORBsupmed.L) were identified as top 5 important brain regions for distinguishing IBS patients from the control group, which are consistent with the brain regions identified in previous literature reviews. We also conducted an external data-driven experiment to further validate the effectiveness of the interpretability module. The results indicate that the selected regions significantly impact IBS.

bioengineering↗

bioRxiv2024

Brain functional connectivity as a mediator between hematological metrics and cognitive decline in children with beta-thalassemia major

Children with beta-thalassemia major ({beta} -TM) are at risk of cognitive impairment, particularly in learning and memory. While cognitive deficits in the general population have been extensively studied, brain-based predictors for {beta}-TM children remain unexplored. This study used connectome-based predictive modeling (CPM) to examine whole-brain functional connectivity in 60 participants to predict cognitive performance. {beta}-TM children showed impaired cognitive abilities, as evidenced by lower Wechsler Intelligence Scale scores compared to controls. The identified brain regions, though not typically linked to cognitive performances, exhibited functional connectivity patterns associated with {beta}-TM, as confirmed by network-based statistics. Correlations between task performance, functional connectivity identified by the CPM, and hematological metrics were also examined. Significant correlations were found between the strength of functional network identified by CPM and hematological metrics, particularly hemoglobin levels and red blood cell distribution width. The study demonstrates that hematological factors influence cognitive performance indirectly through specific functional connectivity, providing new insights into the neural underpinnings of cognitive deficits in children with beta-thalassemia major.

neuroscience↗

bioRxiv2024

Exogenous ephrin-A3 administration restores vaginal epithelial barrier function in progestin-treated mice

Desmosomes are junctional complexes that confer mechanical strength and enhance epithelial barrier function at mucosal surfaces by anchoring intermediate filaments to plasma membrane. While these roles are less explored in vaginal vs. cutaneous epithelium, we previously reported that treating mice with the progestin depot medroxyprogesterone acetate (DMPA) reduces vaginal epithelial levels of the desmosomal cadherins desmoglein-1 (DSG1) and desmocollin-1 (DSC1) and weakens vaginal epithelial barrier function. We also showed these effects were avoided by treating mice with DMPA and a conjugated equine estrogen vaginal cream. The current investigation further explored the effects of sex steroids on vaginal epithelial integrity, identifying ephrin-A3 (EFNA3) as a key regulator of desmosomal cadherin gene expression. We observed topical administration of recombinant EFNA3 (rEFNA3) promotes vaginal DSG1 expression in a biphasic dose-dependent manner and partially reverses the loss of vaginal epithelial barrier function induced by DMPA treatment. Consistent with this effect, morbidity and mortality elicited by genital herpes simplex virus type 2 infection were delayed, but not prevented, in mice administered DMPA and rEFNA3 vs. DMPA and vehicle. Together, these studies identify EFNA3 as an important regulator of desmosomal function in vaginal epithelium and improve current understanding of sex steroid-mediated mechanisms that control vaginal epithelial barrier function.

immunology↗

bioRxiv2024

Mechanism of N-Myc Downstream Regulated Gene-1 regulating Integrin expression to inhibit gastric cancer metastasis

BackgroundN-myc downstream regulated gene-1 (NDRG1), the first member of the NDRG family, is widely distributed in various tissues and organs. In gastric cancer, the hypo-expression of NDRG1 has been positively associated with malignant biological behavior and poor prognosis. In-depth investigation of the potential regulatory mechanism of NDRG1 on gastric cancer is crucial for understanding the pathogenesis of this disease, identifying new therapeutic targets, and developing personalized treatment strategies. This study aims to explore the significance of NDRG1 in regulating the expression of integrins during the progression of gastric cancer. MethodsThe expression of NDRG1 in gastric cancer was analyzed using R software v4.0.3, Boxplot, and the Kaplan-Meier Plotter. Stable cell lines with NDRG1 knockdown and overexpression were subjected to wound healing assays, transwell migration assays, CCK8 assays, and colony formation assays, in order to determine the effects of NDRG1 on the migration and proliferation of gastric cancer cells. Western blotting was employed to examine the impact of NDRG1 on the expression of integrin-related proteins. Immunostaining was used to comprehensively analyze the in vitro experimental results. ResultsThe mRNA and protein levels of NDRG1 were downregulated substantially in gastric cancer, which was inversely correlated with the malignancy of pathological behavior and poor prognosis in gastric cancer. Knockdown of the NDRG1 gene significantly enhanced the proliferation and migration capabilities of gastric cancer cells, whereas overexpression of NDRG1 reduced their metastatic potential and inhibited both migration and proliferation. NDRG1 was found to regulate the expression of fibronectin 1, which in turn influenced the expression of a series of integrins, including v, 5, {beta}1, and {beta}3. This regulatory mechanism may play a crucial role in the early distant metastasis observed in gastric cancer. ConclusionsThis study demonstrated that NDRG1 could regulate the expression levels of integrins through specific signaling pathways, thereby interfering the adhesive and migratory capacities of gastric cancer cells. NDRG1 could serve as a valuable biomarker for the diagnosis and prognosis of gastric cancer, offering new potential targets for its treatment.

cancer biology↗

bioRxiv2024

Auditory working memory mediates the relationship between musicianship and auditory stream segregation

This study investigates the interactions between musicianship and two auditory cognitive mechanisms: auditory working memory (AWM) and stream segregation. The primary hypothesis is that AWM mediates the relationship between musical training and enhanced stream segregation capabilities. Two groups of listeners were tested, the first to establish the relationship between the two variables and the second to replicate the effect in an independent sample. Music history and behavioural data were collected from a total of 145 healthy young adults with normal binaural hearing. They performed a task that requires manipulation of tonal patterns in working memory, and the Music-in-Noise Task (MINT), which measures stream segregation abilities in a musical context. The MINT task expands measurements beyond traditional Speech-in-Noise (SIN) assessments by capturing auditory subskills (e.g., rhythm, visual, spatial, prediction) relevant to stream segregation. Our results showed that musical training is associated with enhanced AWM and MINT task performance, and that this effect is replicable across independent samples. Moreover, we found in both samples that the enhancement of stream segregation was largely mediated by AWM capacity. The results suggest that musical training and/or aptitude enhances music-in-noise perception by way of improved AWM capacity.

neuroscience↗

bioRxiv2024

Connectomic Organization of the Suprachiasmatic Nucleus

The suprachiasmatic nucleus (SCN), the mammalian master clock, is a special structure dedicated to the time computation. However, a connectomic understanding of the nucleus as a whole is lacking. Using serial section electron microscopy, we reconstructed multiscale and multimodal SCN communication networks. Intra-SCN synaptic network consists of 9,566 morphologically similar neurons and 4.3 million synapses, organized into multiscale circuitries that interact with SCN-traversing axon fascicles. Strikingly, SCN neurons engage in unique soma-soma ephaptic interaction, forming 2,038 electrotonic integrative units with the largest overlapping the light-responsive area (LRA). SCNs paracrine modality contains 47,396 m3 dense core vesicles, with notable scarcity in the LRA, suggesting cross-modal coordination and functional integration. These distinct network features provide comprehensive insights into the system architecture of the mammalian circadian clock.

neuroscience↗

bioRxiv2024

CRISPR associated enzymes are mislocalized to the cytoplasm in iPSC-derived neurons resulting in KRAB-specific degradation

The use of CRISPR-associated enzymes in iPSC-derived neurons for precise gene targeting and high-throughput gene perturbation screens offers great potential but presents unique challenges compared to dividing cell lines. CRISPRi screens in iPSC-derived neurons and glia have already been successful in relating gene function to neurological phenotypes; however, loss of dCas9-KRAB expression after differentiation has been observed by many labs and has been largely ascribed to transgene silencing after differentiation. Here, we investigated the expression levels of different CRISPR enzymes in iPSC and Ngn2-derived neurons using piggybac delivery. We found that the commonly used dCas9-KRAB (using the KOX1 domain) displayed dramatic reduction in protein expression levels following neuronal differentiation, yet surprisingly, nCas9 constructs retained comparable protein expression between iPSCs and neurons. We further found that CRISPR constructs, primarily relying on the SV40 Nuclear Localization Signal (NLS), fail to efficiently localize to the nuclei of neurons, despite having robust nuclear levels in iPSCs, leading to KRAB-specific cytoplasmic degradation. By adding a neuronal-specific NLS, we were able to correct neuronal nuclear localization and protein expression, confirming the contribution of mislocalization to the instability of dCas9-KRAB in neurons. As the lack of nuclear localization can have a profound impact on editing and gene perturbation efficiency, we suggest further investigation across both cultured and in-vivo postmitotic cell models.

cell biology↗

bioRxiv2024

Integration of the DD-genome reshapes gene transcription, chromatin architecture and metabolome of allohexaploid wheat leading to enhanced adaptability

The integration, through hybridization, of the DD genome into domesticated tetraploid wheat gave rise to allohexaploid wheat, the most cultivated wheat globally growing across diverse environmental conditions. However, the regulatory basis of this integration on increased environmental adaptability in allohexaploid remains largely unexplored. Here, we investigated the change of transcriptome, epigenome as well as the chromatin interactome, and metabolome in three independent polyploidization events representing DD genome integration. Our findings reveal that polyploidization events induce the activation of defense-related genes through comprehensive reorganization of epigenome and chromatin architecture. DD integration not only brings an additional gene copy but also activates the homoeologs existing in the A and B subgenomes through chromatin interactions. Furthermore, secondary metabolites represented by alkaloids and flavonoids that are crucial for environmental adaptation, are significantly enriched following polyploidization. Thus, hexaploid wheat exhibits enhanced tolerance to alkalinity, UV-B light stress and high salt conditions was observed. These results highlight the indispensable role of DD genome integration in the adaptability of allohexaploid wheat during its evolution.

plant biology↗