Glycoprotein E-Displaying Nanoparticles Induce Robust Neutralizing Antibodies and T-Cell Response against Varicella Zoster Virus.

The Varicella zoster virus (VZV), responsible for both varicella (chickenpox) and herpes zoster (shingles), presents significant global health challenges. While primary VZV infection primarily affects children, leading to chickenpox, reactivation in later life can result in herpes zoster and associated post-herpetic neuralgia, among other complications. Vaccination remains the most effective strategy for VZV prevention, with current vaccines largely based on the attenuated vOka strains. Although these vaccines are generally effective, they can induce varicella-like rashes and have sparked concerns regarding cell virulence. As a safer alternative, subunit vaccines circumvent these issues. In this study, we developed a nanoparticle-based vaccine displaying the glycoprotein E (gE) on ferritin particles using the SpyCatcher/SpyTag system, termed FR-gE. This FR-gE nanoparticle antigen elicited substantial gE-specific binding and VZV-neutralizing antibody responses in BALB/c and C57BL/6 mice-responses that were up to 3.2-fold greater than those elicited by the subunit gE while formulated with FH002C, aluminum hydroxide, or a liposome-based XUA01 adjuvant. Antibody subclass analysis revealed that FR-gE produced comparable levels of IgG1 and significantly higher levels of IgG2a compared to subunit gE, indicating a Th1-biased immune response. Notably, XUA01-adjuvanted FR-gE induced a significant increase in neutralizing antibody response compared to the live attenuated varicella vaccine and recombinant vaccine, Shingrix. Furthermore, ELISPOT assays demonstrated that immunization with FR-gE/XUA01 generated IFN-γ and IL-2 levels comparable to those induced by Shingrix. These findings underscore the potential of FR-gE as a promising immunogen for the development of varicella and herpes zoster vaccines.

A Quantitative Computational Framework for Allopolyploid Single-Cell Data Integration and Core Gene Ranking in Development.

Polyploidization drives regulatory and phenotypic innovation. How the merger of different genomes contributes to polyploid development is a fundamental issue in evolutionary developmental biology and breeding research. Clarifying this issue is challenging because of genome complexity and the difficulty in tracking stochastic subgenome divergence during development. Recent single-cell sequencing techniques enabled probing subgenome-divergent regulation in the context of cellular differentiation. However, analyzing single-cell data suffers from high error rates due to high dimensionality, noise, and sparsity, and the errors stack up in polyploid analysis due to the increased dimensionality of comparisons between subgenomes of each cell, hindering deeper mechanistic understandings. In this study, we develop a quantitative computational framework, called "pseudo-genome divergence quantification" (pgDQ), for quantifying and tracking subgenome divergence directly at the cellular level. Further comparing with cellular differentiation trajectories derived from single-cell RNA sequencing data allows for an examination of the relationship between subgenome divergence and the progression of development. pgDQ produces robust results and is insensitive to data dropout and noise, avoiding high error rates due to multiple comparisons of genes, cells, and subgenomes. A statistical diagnostic approach is proposed to identify genes that are central to subgenome divergence during development, which facilitates the integration of different data modalities, enabling the identification of factors and pathways that mediate subgenome-divergent activity during development. Case studies have demonstrated that applying pgDQ to single-cell and bulk tissue transcriptomic data promotes a systematic and deeper understanding of how dynamic subgenome divergence contributes to developmental trajectories in polyploid evolution.

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Central precocious puberty (CPP) is a developmental disorder caused by early activation of the hypothalamic-pituitary-gonadal axis. The incidence of CPP is rapidly increasing, but the underlying mechanisms are not fully understood. Previous studies have shown that gain-of-function mutations in the KISS1R and KISS1 genes and loss-of-function mutations in the MKRN3, LIN28, and DLK1 genes may lead to early initiation of pubertal development. Recent research has also revealed the significant role of epigenetic factors such as DNA methylation and microRNAs in the regulation of gonadotropin-releasing hormone neurons, as well as the modulating effect of gene networks involving multiple variant genes on pubertal initiation. This review summarizes the genetic etiology and pathogenic mechanisms underlying CPP.

Prevalence and Correlators of Diabetes Distress in Adults with Type 2 Diabetes: A Cross-Sectional Study.

Purpose: To address the prevalence of diabetes distress (DD) and its correlators in adults with type 2 diabetes. Patients and Methods: During 2021 and 2022, we conducted a cross-sectional study in three Class A tertiary comprehensive hospitals in China, and received 947 participants who completed a printed survey covering DD, demographic, diabetic, physiological, and psychosocial factors. We used Jonckheere-Terpstra, chi-square, and Fisher's exact tests to assess intergroup differences between different levels of DD. We used ordinal logistic regression analysis to analyze correlators of DD further. Results: The prevalence of DD was 34.64%. In univariate analysis, those with lower satisfaction with financial status, longer durations of diabetes, more complications, higher glycemia, more severe insomnia, treatment by medications only, poorer lifestyle interventions, fewer self-care activities, more types and frequencies of insulin injections, and spending more money and time on treatment were susceptible to DD. Type D personality, negative illness perceptions, negative coping styles, and psychological effects of major life events were related to higher DD. Hope, self-efficacy, positive coping styles, and social support can reduce DD. In ordinal logistic regression analysis, hypoglycemic episode (ß=-1.118, p=0.019, "have hypoglycemic" as reference) and Brief Illness Perception Questionnaire (ß=0.090, p<0.001) were significant positive correlators for DD, while diet intervention (ß=0.803, p=0.022, "have diet intervention" as reference), money spent on diabetes treatment (ß<-0.001, p=0.035), and SES (ß=-0.257, p<0.001) were significant negative correlators. Conclusion: More than one-third of Chinese adults with type 2 diabetes experience moderate or high levels of DD. DD was associated with financial, diabetic, physiological, and psychosocial status.

LHP1-mediated epigenetic buffering of subgenome diversity and defense responses confers genome plasticity and adaptability in allopolyploid wheat.

Polyploidization is a major driver of genome diversification and environmental adaptation. However, the merger of different genomes may result in genomic conflicts, raising a major question regarding how genetic diversity is interpreted and regulated to enable environmental plasticity. By analyzing the genome-wide binding of 191 trans-factors in allopolyploid wheat, we identified like heterochromatin protein 1 (LHP1) as a master regulator of subgenome-diversified genes. Transcriptomic and epigenomic analyses of LHP1 mutants reveal its role in buffering the expression of subgenome-diversified defense genes by controlling H3K27me3 homeostasis. Stripe rust infection releases latent subgenomic variations by eliminating H3K27me3-related repression. The simultaneous inactivation of LHP1 homoeologs by CRISPR-Cas9 confers robust stripe rust resistance in wheat seedlings. The conditional repression of subgenome-diversified defenses ensures developmental plasticity to external changes, while also promoting neutral-to-non-neutral selection transitions and adaptive evolution. These findings establish an LHP1-mediated buffering system at the intersection of genotypes, environments, and phenotypes in polyploid wheat. Manipulating the epigenetic buffering capacity offers a tool to harness cryptic subgenomic variations for crop improvement.

Transposable element-initiated enhancer-like elements generate the subgenome-biased spike specificity of polyploid wheat.

Transposable elements (TEs) comprise ~85% of the common wheat genome, which are highly diverse among subgenomes, possibly contribute to polyploid plasticity, but the causality is only assumed. Here, by integrating data from gene expression cap analysis and epigenome profiling via hidden Markov model in common wheat, we detect a large proportion of enhancer-like elements (ELEs) derived from TEs producing nascent noncoding transcripts, namely ELE-RNAs, which are well indicative of the regulatory activity of ELEs. Quantifying ELE-RNA transcriptome across typical developmental stages reveals that TE-initiated ELE-RNAs are mainly from RLG_famc7.3 specifically expanded in subgenome A. Acquisition of spike-specific transcription factor binding likely confers spike-specific expression of RLG_famc7.3-initiated ELE-RNAs. Knockdown of RLG_famc7.3-initiated ELE-RNAs resulted in global downregulation of spike-specific genes and abnormal spike development. These findings link TE expansion to regulatory specificity and polyploid developmental plasticity, highlighting the functional impact of TE-driven regulatory innovation on polyploid evolution.

Genome and transcriptome of Selaginella kraussiana reveal evolution of root apical meristems in vascular plants.

The evolution of roots allowed vascular plants to adapt to land environments. Fossil evidence indicates that roots evolved independently in euphyllophytes (ferns and seed plants) and lycophytes, the two lineages of extant vascular plants. Based on a high-quality genome assembly, mRNA sequencing (mRNA-seq) data, and single-cell RNA-seq data for the lycophyte Selaginella kraussiana, we show that the two root origin events in lycophytes and euphyllophytes adopted partially similar molecular modules in the regulation of root apical meristem (RAM) development. In S. kraussiana, the RAM initiates from the rhizophore primordium guided by auxin and duplicates itself by dichotomous branching. The auxin signaling pathway directly upregulates euAINTEGUMENTAb (SkeuANTb), and then SkeuANTb directly promotes the expression of SkeuANTa and the WUSCHEL-RELATED HOMEOBOX13b (SkWOX13b) for RAM maintenance, partially similar to the molecular pathway involving the euANT-branch PLETHORA (AtPLT) genes and AtWOX5 in root initiation in the seed plant Arabidopsis thaliana. Other molecular modules, e.g., SHORT-ROOT and SCARECROW, also have partially similar expression patterns in the RAMs of S. kraussiana and A. thaliana. Overall, our study not only provides genome and transcriptome tools of S. kraussiana but also indicates the employment of some common molecular modules in RAMs during root origins in lycophytes and euphyllophytes.

Target-triggered 'colorimetric-fluorescence' dual-signal sensing system based on the versatility of MnO2 nanosheets for rapid detection of uric acid.

A simple dual-signal assay that combined colorimetric and fluorometric strategy for uric acid (UA) rapid detection was designed based on the versatility of facile synthesized MnO2 nanosheet. The oxidization of 3,3',5,5'-tetramethylbenzidine (TMB) and the fluorescence quenching of quantum dots (QDs) occurred simultaneously in the presence of MnO2 nanosheet. UA could decompose MnO2 nanosheet into Mn2+, resulting in the fluorescence recovery of QDs, along with the fading of the blue color of ox TMB. Based on the principles above, the detection of UA could be realized by the change of the dual signals (colorimetric and fluorometric). The linear range of the colorimetric mode was 5-60 µmol L-1, and the limit of detection (LOD) was 2.65 µmol L-1; the linear range of the fluorescence mode was wide at 5-120 µmol L-1, and the LOD could be as low as 1.33 µmol L-1. The method was successfully used for analyzing UA levels in human serum samples, indicating that this new dual-signal method could be applied in clinical diagnosis.

Metabolic functional redundancy of the CYP9A subfamily members leads to P450-mediated lambda-cyhalothrin resistance in Cydia pomonella.

BACKGROUND: The evolution of insect resistance to pesticides poses a continuing threat to sustainable pest management. While much is known about the molecular mechanisms that confer resistance in model insects and few agricultural pests, far less is known about fruit pests. Field-evolved resistance to synthetic insecticides such as lambda-cyhalothrin has been widely documented in Cydia pomonella, a major invasive pest of pome fruit worldwide, and the increased production of cytochrome P450 monooxygenases (P450s) has been linked to resistance in field-evolved resistant populations. However, the underlying molecular mechanisms of P450-mediated insecticide resistance remain largely unknown. RESULTS: Here we found that functional redundancy and preference of metabolism by P450s genes in the CYP9A subfamily confer resistance to lambda-cyhalothrin in Cydia pomonella. A total of four CYP9A genes, including CYP9A61, CYP9A120, CYP9A121, and CYP9A122, were identified from Cydia pomonella. Among these, CYP9A120, CYP9A121, and CYP9A122 were predominantly expressed in the midgut of larvae. The expression levels of these P450 genes were significantly induced by a lethal dose that would kill 10% (LD10 ) of lambda-cyhalothrin and were overexpressed in a field-evolved lambda-cyhalothrin resistant population. Knockdown of CYP9A120 and CYP9A121 by RNA-mediated interference (RNAi) increased the susceptibility of larvae to lambda-cyhalothrin. In vitro assays demonstrated that recombinant P450s expressed in Sf9 cells can metabolize lambda-cyhalothrin, but with functional redundancy and divergence through regioselectivity of metabolism. CYP9A121 preferred to convert lambda-cyhalothrin to 2'-hydroxy-lambda-cyhalothrin, whereas CYP9A122 only generated 4'-hydroxy metabolite of lambda-cyhalothrin. Although possesses a relatively low metabolic capability, CYP9A120 balanced catalytic competence to generate both 2'- and 4'-metabolites. CONCLUSION: Collectively, these results reveal that metabolic functional redundancy of three members of the CYP9A subfamily leads to P450-mediated lambda-cyhalothrin resistance in Cydia pomonella, thus representing a potential adaptive evolutionary strategy during its worldwide expansion. © 2022 Society of Chemical Industry.

Metabolome and transcriptome integration reveals insights into the process of delayed petal abscission in rose by STS.

The abscission of plant organs plays an important role in ensuring the normal life activities. Rose is one of the most important ornamental plants, and its premature abscission of petal has seriously affected the quality and commercial value. Silver Thiosulfate (STS) is an ethylene inhibitor, which is often used preservative to delay the senescence of fresh cut flowers. To understand the regulatory mechanism of petal abscission in rose by STS, integrative analysis of the metabolome and transcriptome profiles was performed in abscission zone (AZ) tissues of rose under different treatments (MOCK, STS, ETH, STS+ETH). The results showed that STS significantly delayed the petal abscission in phenotype and reduced the activity of two enzymes (pectinase and cellulase) associated with cell wall degradation in physiological level. STS affected the contents of five metabolites (shikonin, jasmonic acid, gluconolactone, stachyose and D-Erythrose 4-phosphate), and involved changes in the expression of 39 differentially expressed genes (DEGs) associated with these five metabolites. Five DEGs (LOC112192149, LOC112196726, LOC112189737, LOC112188495, and LOC112188936) were probably directly associated with the biosynthesis of shikonin, jasmonic acid, and D-Erythrose 4-phosphate. Meanwhile, the effect of STS on the abscission process significantly involved in the pentose phosphate pathway and amino acid biosynthesis pathway. In addition, STS had a greater effect on the transcription factors, phytohormone related DEGs represented by auxin and ethylene, DEGs related to disease resistance and amino acid, etc. Above all, STS negatively influences petal abscission of rose, these results maybe provide a reference for subsequent studies on petal abscission of rose by STS.

Transposable elements orchestrate subgenome-convergent and -divergent transcription in common wheat.

The success of common wheat as a global staple crop was largely attributed to its genomic diversity and redundancy due to the merge of different genomes, giving rise to the major question how subgenome-divergent and -convergent transcription is mediated and harmonized in a single cell. Here, we create a catalog of genome-wide transcription factor-binding sites (TFBSs) to assemble a common wheat regulatory network on an unprecedented scale. A significant proportion of subgenome-divergent TFBSs are derived from differential expansions of particular transposable elements (TEs) in diploid progenitors, which contribute to subgenome-divergent transcription. Whereas subgenome-convergent transcription is associated with balanced TF binding at loci derived from TE expansions before diploid divergence. These TFBSs have retained in parallel during evolution of each diploid, despite extensive unbalanced turnover of the flanking TEs. Thus, the differential evolutionary selection of paleo- and neo-TEs contribute to subgenome-convergent and -divergent regulation in common wheat, highlighting the influence of TE repertory plasticity on transcriptional plasticity in polyploid.

Genetic engineering of baculovirus-insect cell system to improve protein production.

The Baculovirus Expression Vector System (BEVS), a mature foreign protein expression platform, has been available for decades, and has been effectively used in vaccine production, gene therapy, and a host of other applications. To date, eleven BEVS-derived products have been approved for use, including four human vaccines [Cervarix against cervical cancer caused by human papillomavirus (HPV), Flublok and Flublok Quadrivalent against seasonal influenza, Nuvaxovid/Covovax against COVID-19], two human therapeutics [Provenge against prostate cancer and Glybera against hereditary lipoprotein lipase deficiency (LPLD)] and five veterinary vaccines (Porcilis Pesti, BAYOVAC CSF E2, Circumvent PCV, Ingelvac CircoFLEX and Porcilis PCV). The BEVS has many advantages, including high safety, ease of operation and adaptable for serum-free culture. It also produces properly folded proteins with correct post-translational modifications, and can accommodate multi-gene- or large gene insertions. However, there remain some challenges with this system, including unstable expression and reduced levels of protein glycosylation. As the demand for biotechnology increases, there has been a concomitant effort into optimizing yield, stability and protein glycosylation through genetic engineering and the manipulation of baculovirus vector and host cells. In this review, we summarize the strategies and technological advances of BEVS in recent years and explore how this will be used to inform the further development and application of this system.

Identification of a cross-neutralizing antibody that targets the receptor binding site of H1N1 and H5N1 influenza viruses.

Influenza A viruses pose a significant threat globally each year, underscoring the need for a vaccine- or antiviral-based broad-protection strategy. Here, we describe a chimeric monoclonal antibody, C12H5, that offers neutralization against seasonal and pandemic H1N1 viruses, and cross-protection against some H5N1 viruses. Notably, C12H5 mAb offers broad neutralizing activity against H1N1 and H5N1 viruses by controlling virus entry and egress, and offers protection against H1N1 and H5N1 viral challenge in vivo. Through structural analyses, we show that C12H5 engages hemagglutinin (HA), the major surface glycoprotein on influenza, at a distinct epitope overlapping the receptor binding site and covering the 140-loop. We identified eight highly conserved (~90%) residues that are essential for broad H1N1 recognition, with evidence of tolerance for Asp or Glu at position 190; this site is a molecular determinant for human or avian host-specific recognition and this tolerance endows C12H5 with cross-neutralization potential. Our results could benefit the development of antiviral drugs and the design of broad-protection influenza vaccines.

Baculovirus Display of Varicella-Zoster Virus Glycoprotein E Induces Robust Humoral and Cellular Immune Responses in Mice.

Varicella-zoster virus (VZV) is the causative agent of varicella and herpes zoster (HZ) and can pose a significant challenge to human health globally. The initial VZV infection-more common in children-causes a self-limiting chicken pox. However, in later life, the latent VZV can become reactivated in these patients, causing HZ and postherpetic neuralgia (PHN), a serious and painful complication. VZV glycoprotein E (gE) has been developed into a licensed subunit vaccine against HZ (Shingrix). However, its efficacy relies on the concomitant delivery of a robust adjuvant (AS01B). Here, we sought to create a new immunogen for vaccine design by displaying the VZV-gE on the baculovirus surface (Bac-gE). Correct localization and display of gE on the engineered baculovirus was verified by flow cytometry and immune electron microscopy. We show that Bac-gE provides excellent antigenicity against VZV and induces not only stronger gE-specific CD4+ and CD8+ T cell responses but also higher levels of VZV-specific neutralizing antibodies as compared with other vaccine strategies in mice. Collectively, we show that the baculovirus display of VZV-gE confers ideal humoral and cellular immune responses required for HZ vaccine development, paving the way for a baculovirus-based vaccine design.

The Chinese version of the revised Diabetes Distress Scale for adults with type 2 diabetes: Translation and validation study.

Objectives: This study aimed to translate the revised 17-item Diabetes Distress Scale (DDS17, 2017) into mandarin (simplified) Chinese and validate the Chinese version of DDS17 (C-DDS17, 2021) among adult patients with type 2 diabetes in China. Methods: A scale translation and cross-sectional validation study was conducted. The DDS17 was translated into mandarin (simplified) Chinese through a five-step process: authorization, forward translation, synthesis, back translation, and amendment. During this session, 59 patients assessed the understandability and readability of the translated scale. From June 7 to September 4, 2021, a cross-sectional study that adhered to the COSMIN checklist was conducted with 400 individuals with type 2 diabetes from three Class A tertiary comprehensive hospitals in Beijing, China. The content, construct, convergent, discriminant validity, and reliability (Cronbach's α coefficient and item-total correlation coefficients) of the C-DDS17 were evaluated. This study was a part of a project registered in the Chinese Clinical Trial Registry (no. ChiCTR2100047071). Results: Among the participants, 33.3% (133/400) of them experienced moderate to high diabetes distress. The content validity indices of the C-DDS17 equaled 1.00. The scale yielded a four-factor structure. The average variances extracted were 0.42-0.57, which was lower than squared correlations. Cronbach's α coefficient was 0.88 for the overall scale and ranged from 0.76 to 0.81 for sub-scales. Corrected item-total correlation coefficients ranged from 0.42 to 0.61. The eighth item ("Feeling that I am often failing with my diabetes routine") was better fit to physician distress than regimen distress but had little influence on the validation results. Conclusions: The C-DDS17 is a reliable and valid instrument for assessing diabetes distress in patients with type 2 diabetes. It is a promising instrument for early identification and management of diabetes distress in clinical practice and trials.

Transcriptional landscapes of de novo root regeneration from detached Arabidopsis leaves revealed by time-lapse and single-cell RNA sequencing analyses.

Detached Arabidopsis thaliana leaves can regenerate adventitious roots, providing a platform for studying de novo root regeneration (DNRR). However, the comprehensive transcriptional framework of DNRR remains elusive. Here, we provide a high-resolution landscape of transcriptome reprogramming from wound response to root organogenesis in DNRR and show key factors involved in DNRR. Time-lapse RNA sequencing (RNA-seq) of the entire leaf within 12 h of leaf detachment revealed rapid activation of jasmonate, ethylene, and reactive oxygen species (ROS) pathways in response to wounding. Genetic analyses confirmed that ethylene and ROS may serve as wound signals to promote DNRR. Next, time-lapse RNA-seq within 5 d of leaf detachment revealed the activation of genes involved in organogenesis, wound-induced regeneration, and resource allocation in the wounded region of detached leaves during adventitious rooting. Genetic studies showed that BLADE-ON-PETIOLE1/2, which control aboveground organs, PLETHORA3/5/7, which control root organogenesis, and ETHYLENE RESPONSE FACTOR115, which controls wound-induced regeneration, are involved in DNRR. Furthermore, single-cell RNA-seq data revealed gene expression patterns in the wounded region of detached leaves during adventitious rooting. Overall, our study not only provides transcriptome tools but also reveals key factors involved in DNRR from detached Arabidopsis leaves.

Cross-neutralizing antibodies bind a SARS-CoV-2 cryptic site and resist circulating variants.

The emergence of numerous variants of SARS-CoV-2, the causative agent of COVID-19, has presented new challenges to the global efforts to control the COVID-19 pandemic. Here, we obtain two cross-neutralizing antibodies (7D6 and 6D6) that target Sarbecoviruses' receptor-binding domain (RBD) with sub-picomolar affinities and potently neutralize authentic SARS-CoV-2. Crystal structures show that both antibodies bind a cryptic site different from that recognized by existing antibodies and highly conserved across Sarbecovirus isolates. Binding of these two antibodies to the RBD clashes with the adjacent N-terminal domain and disrupts the viral spike. Both antibodies confer good resistance to mutations in the currently circulating SARS-CoV-2 variants. Thus, our results have direct relevance to public health as options for passive antibody therapeutics and even active prophylactics. They can also inform the design of pan-sarbecovirus vaccines.

Evolutionary rewiring of the wheat transcriptional regulatory network by lineage-specific transposable elements.

More than 80% of the wheat genome consists of transposable elements (TEs), which act as major drivers of wheat genome evolution. However, their contributions to the regulatory evolution of wheat adaptations remain largely unclear. Here, we created genome-binding maps for 53 transcription factors (TFs) underlying environmental responses by leveraging DAP-seq in Triticum urartu, together with epigenomic profiles. Most TF binding sites (TFBSs) located distally from genes are embedded in TEs, whose functional relevance is supported by purifying selection and active epigenomic features. About 24% of the non-TE TFBSs share significantly high sequence similarity with TE-embedded TFBSs. These non-TE TFBSs have almost no homologous sequences in non-Triticeae species and are potentially derived from Triticeae-specific TEs. The expansion of TE-derived TFBS linked to wheat-specific gene responses, suggesting TEs are an important driving force for regulatory innovations. Altogether, TEs have been significantly and continuously shaping regulatory networks related to wheat genome evolution and adaptation.

An atlas of wheat epigenetic regulatory elements reveals subgenome divergence in the regulation of development and stress responses.

Wheat (Triticum aestivum) has a large allohexaploid genome. Subgenome-divergent regulation contributed to genome plasticity and the domestication of polyploid wheat. However, the specificity encoded in the wheat genome determining subgenome-divergent spatio-temporal regulation has been largely unexplored. The considerable size and complexity of the genome are major obstacles to dissecting the regulatory specificity. Here, we compared the epigenomes and transcriptomes from a large set of samples under diverse developmental and environmental conditions. Thousands of distal epigenetic regulatory elements (distal-epiREs) were specifically linked to their target promoters with coordinated epigenomic changes. We revealed that subgenome-divergent activity of homologous regulatory elements is affected by specific epigenetic signatures. Subgenome-divergent epiRE regulation of tissue specificity is associated with dynamic modulation of H3K27me3 mediated by Polycomb complex and demethylases. Furthermore, quantitative epigenomic approaches detected key stress responsive cis- and trans-acting factors validated by DNA Affinity Purification and sequencing, and demonstrated the coordinated interplay between epiRE sequence contexts, epigenetic factors, and transcription factors in regulating subgenome divergent transcriptional responses to external changes. Together, this study provides a wealth of resources for elucidating the epiRE regulomics and subgenome-divergent regulation in hexaploid wheat, and gives new clues for interpreting genetic and epigenetic interplay in regulating the benefits of polyploid wheat.