Modified mRNA-based gene editing reveals sarcomere-based regulation of gene expression in human induced-pluripotent stem cell-derived cardiomyocytes.

Mutations in genes coding sarcomere components are the major causes of human inherited cardiomyopathy. Genome editing is widely applied to genetic modification of human pluripotent stem cells (hPSCs) before hPSCs were differentiated into cardiomyocytes to model cardiomyopathy. Whether genetic mutations influence the early hPSC differentiation process or solely the terminally differentiated cardiomyocytes during cardiac pathogenesis remains challenging to distinguish. To solve this problem, here we harnessed chemically modified mRNA (modRNA) and synthetic single-guide RNA to develop an efficient genome editing approach in hPSC-derived cardiomyocytes (hPSC-CMs). We showed that modRNA-based CRISPR/Cas9 mutagenesis of TNNT2, the coding gene for cardiac troponin T, results in sarcomere disassembly and contractile dysfunction in hPSC-CMs. These structural and functional phenotypes were associated with profound downregulation of oxidative phosphorylation genes and upregulation of cardiac stress markers NPPA and NPPB. These data confirmed that sarcomeres regulate gene expression in hPSC-CMs and highlighted the RNA technology as a powerful tool to achieve stage-specific genome editing during hPSC differentiation.

Deformable Joule heating electrode based on hybrid layers of silver nanowires and carbon nanotubes and its application in a refreshable multi-cell Braille display.

Stretchable electrodes are an essential component in soft actuator systems. In particular, Joule heating electrodes (JHEs) are required for thermal actuation systems. A highly stretchable, patternable, and low-voltage operating JHE based on hybrid layers of silver nanowires (AgNWs) and carbon nanotubes (CNTs) is reported. The conductive layers were applied on a locally pre-strained bistable electroactive polymer (BSEP) membrane to form a wrinkled conductive surface with a low resistance of 300 Ω/sq, and subsequently patterned to a serpentine trace by laser engraving. The resistance of the resulting electrode remains nearly unchanged up to ~80-90% area strain. By applying a voltage of 7 - 9 V to the electrode, the temperature of the BSEP membrane increased to more than 60 °C, well above the polymer's phase transition temperature of 46 °C, thereby lowering its modulus by a factor of 103. An electronic Braille device based on the JHEs on a BSEP membrane was assembled with a diaphragm chamber. The electrode was patterned into 3 × 2 individually addressable pixels according to the standard U.S. Braille cell format. Through Joule heating of the pixels and local expansion of the BSEP membrane using a small pneumatic pressure, the pixels deformed out of the plane by over 0.5 mm to display specific Braille letters. The Braille content can be refreshed for 20,000 cycles at the same operating voltage.

Haptic artificial muscle skin for extended reality.

Existing haptic actuators are often rigid and limited in their ability to replicate real-world tactile sensations. We present a wearable haptic artificial muscle skin (HAMS) based on fully soft, millimeter-scale, multilayer dielectric elastomer actuators (DEAs) capable of significant out-of-plane deformation, a capability that typically requires rigid or liquid biasing. The DEAs use a thickness-varying multilayer structure to achieve large out-of-plane displacement and force, maintaining comfort and wearability. Experimental results demonstrate that HAMS can produce complex tactile feedback with high perception accuracy. Moreover, we show that HAMS can be integrated into extended reality (XR) systems, enhancing immersion and offering potential applications in entertainment, education, and assistive technologies.

Enhanced Water Resistance of TiO2-GO-SMS-Modified Soil Composite for Use as a Repair Material in Earthen Sites.

Most earthen sites are located in open environments eroded by wind and rain, resulting in spalling and cracking caused by shrinkage due to constant water absorption and loss. Together, these issues seriously affect the stability of such sites. Gypsum-lime-modified soil offers relatively strong mechanical properties but poor water resistance. If such soil becomes damp or immersed in water, its strength is significantly reduced, making it unviable for use as a material in the preparation of earthen sites. In this study, we achieved the composite addition of a certain amount of sodium methyl silicate (SMS), titanium dioxide (TiO2), and graphene oxide (GO) into gypsum-lime-modified soil and analyzed the microstructural evolution of the composite-modified soil using characterization methods such as XRD, SEM, and EDS. A comparative study was conducted on changes in the mechanical properties of the composite-modified soil and original soil before and after immersion using water erosion, unconfined compression (UCS), and unconsolidated undrained (UU) triaxial compression tests. These analyses revealed the micro-mechanisms for improving the waterproof performance of the composite-modified soil. The results showed that the addition of SMS, TiO2, and GO did not change the crystal structure or composition of the original soil. In addition, TiO2 and GO were evenly distributed between the modified soil particles, playing a positive role in filling and stabilizing the structure of the modified soil. After being immersed in water for one hour, the original soil experienced structural instability leading to collapse. While the water absorption rate of the composite-modified soil was only 0.84%, its unconfined compressive strength was 4.88 MPa (the strength retention rate before and after immersion was as high as 93.1%), and the shear strength was 614 kPa (the strength retention rate before and after immersion was as high as 96.7%).

Detecting and quantifying PM2.5 and NO2 contributions from train and road traffic in the vicinity of a major railway terminal in Dublin, Ireland.

Air pollution from transport hubs is a recognised health concern for local urban inhabitants. Within the domain of transport hubs, significant attention has been given to larger airport and port settings, however concerns have been raised about emissions from urban railway hubs, especially those with diesel trains. This paper presents an approach that adopts low-cost monitoring (LCM) for fixed site monitoring (FSM) to quantify and disaggregate PM2.5 and NO2 contributions from railway station and road traffic on air quality in the vicinity of railway station in Dublin, Ireland. The NO2 sensor showed larger discrepancies than the PM2.5 sensor when compared to the reference monitor. Machine learning models (XGBoost and Random Forest (RF) regression) were applied to calibrate the LCM devices, with the XGBoost model (NO2, R2 = 0.8 and RSME = 9.1 µg/m3 & PM2.5, R2 = 0.92 and RSME = 2.2 µg/m3) deemed more appropriate than the RF model. Local wind conditions, pressure, PM2.5 concentrations, and road traffic significantly impacted NO2 model results, while raw PM2.5 sensor readings greatly influenced the PM2.5 model output. This highlights that the NO2 sensor requires more input data for accurate calibration, unlike the PM2.5 sensor. The monitoring results from the one-month monitoring campaign from May 25, 2023 to June 25, 2023 presented elevated NO2 and PM2.5 concentrations measured at the railway station, which translated to exceedances of the annual WHO limits (PM2.5 = 5 µg/m3, NO2 = 10 µg/m3) by 1.6-1.8 and 3.2-5.2 times respectively at the study site. A subsequent data filtering technique based on wind orientation, revealed that the railway station was the main PM2.5 source and road traffic was the main NO2 source when winds come from the railway station. This study highlights the value of LCM devices alongside robust machine learning techniques to capture air quality in urban settings.

Filamentous Actin in the Nucleus in Triple-Negative Breast Cancer Stem Cells: A Key to Drug-Induced Nucleolar Stress and Stemness Inhibition?

Actin, primarily a cytoplasmic cytoskeleton protein, is transported in and out of the nucleus with the help of actin-binding proteins (ABPs). Actin exists in two forms, i.e., monomeric globular (G-actin) and polymerized filamentous (F-actin). While G-actin promotes gene transcription by associating with RNA polymerases, F-actin can inhibit this effect in the nucleus. Unexpectedly, we found that lovastatin, an FDA-approved lipid-lowering drug, induces actin redistribution and its translocation into the nucleus in triple-negative breast cancer (TNBC) cancer stem cells. Lovastatin treatment also decreased levels of rRNAs and stemness markers, which are transcription products of RNA Pol I and Pol II, respectively. Bioinformatics analysis showed that actin genes were positively correlated with ABP genes involved in the translocation/polymerization and transcriptional regulation of nuclear actin in breast cancer. Similar correlations were found between actin genes and RNA Pol I genes and stemness-related genes. We propose a model to explain the roles of lovastatin in inducing nucleolar stress and inhibiting stemness in TNBC cancer stem cells. In our model, lovastatin induces translocation/accumulation of F-actin in the nucleus/nucleolus, which, in turn, induces nucleolar stress and stemness inhibition by suppressing the synthesis of rRNAs and decreasing the expression of stemness-related genes. Our model has opened up a new field of research on the roles of nuclear actin in cancer biology, offering potential therapeutic targets for the treatment of TNBC.

Annexin A1 binds PDZ and LIM domain 7 to inhibit adipogenesis and prevent obesity.

Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.

Estimating rainfall intensity based on surveillance audio and deep-learning.

Rainfall data with high spatial and temporal resolutions are essential for urban hydrological modeling. Ubiquitous surveillance cameras can continuously record rainfall events through video and audio, so they have been recognized as potential rain gauges to supplement professional rainfall observation networks. Since video-based rainfall estimation methods can be affected by variable backgrounds and lighting conditions, audio-based approaches could be a supplement without suffering from these conditions. However, most audio-based approaches focus on rainfall-level classification rather than rainfall intensity estimation. Here, we introduce a dataset named Surveillance Audio Rainfall Intensity Dataset (SARID) and a deep learning model for estimating rainfall intensity. First, we created the dataset through audio of six real-world rainfall events. This dataset's audio recordings are segmented into 12,066 pieces and annotated with rainfall intensity and environmental information, such as underlying surfaces, temperature, humidity, and wind. Then, we developed a deep learning-based baseline using Mel-Frequency Cepstral Coefficients (MFCC) and Transformer architecture to estimate rainfall intensity from surveillance audio. Validated from ground truth data, our baseline achieves a root mean absolute error of 0.88 mm h-1 and a coefficient of correlation of 0.765. Our findings demonstrate the potential of surveillance audio-based models as practical and effective tools for rainfall observation systems, initiating a new chapter in rainfall intensity estimation. It offers a novel data source for high-resolution hydrological sensing and contributes to the broader landscape of urban sensing, emergency response, and resilience.

In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-disc-associated mitigator of isoproterenol-induced cardiac injury.

Z-discs are core ultrastructural organizers of cardiomyocytes that modulate many facets of cardiac pathogenesis. Yet a comprehensive proteomic atlas of Z-disc-associated components remain incomplete. Here, we established an adeno-associated virus (AAV)-delivered, cardiomyocyte-specific, proximity-labeling approach to characterize the Z-disc proteome in vivo. We found palmdelphin (PALMD) as a novel Z-disc-associated protein in both adult murine cardiomyocytes and human pluripotent stem cell-derived cardiomyocytes. Germline and cardiomyocyte-specific Palmd knockout mice were grossly normal at baseline but exhibited compromised cardiac hypertrophy and aggravated cardiac injury upon long-term isoproterenol treatment. By contrast, cardiomyocyte-specific PALMD overexpression was sufficient to mitigate isoproterenol-induced cardiac injury. PALMD ablation perturbed the transverse tubule (T-tubule)-sarcoplasmic reticulum (SR) ultrastructures, which formed the Z-disc-associated junctional membrane complex (JMC) essential for calcium handling and cardiac function. These phenotypes were associated with the reduction of nexilin (NEXN), a crucial Z-disc-associated protein that is essential for both Z-disc and JMC structures and functions. PALMD interacted with NEXN and enhanced its protein stability while the Nexn mRNA level was not affected. AAV-based NEXN addback rescued the exacerbated cardiac injury in isoproterenol-treated PALMD-depleted mice. Together, this study discovered PALMD as a potential target for myocardial protection and highlighted in vivo proximity proteomics as a powerful approach to nominate novel players regulating cardiac pathogenesis.

Unveiling Organic Electrode Materials in Aqueous Zinc-Ion Batteries: From Structural Design to Electrochemical Performance.

Aqueous zinc-ion batteries (AZIBs) are one of the most compelling alternatives of lithium-ion batteries due to their inherent safety and economics viability. In response to the growing demand for green and sustainable energy storage solutions, organic electrodes with the scalability from inexpensive starting materials and potential for biodegradation after use have become a prominent choice for AZIBs. Despite gratifying progresses of organic molecules with electrochemical performance in AZIBs, the research is still in infancy and hampered by certain issues due to the underlying complex electrochemistry. Strategies for designing organic electrode materials for AZIBs with high specific capacity and long cycling life are discussed in detail in this review. Specifically, we put emphasis on the unique electrochemistry of different redox-active structures to provide in-depth understanding of their working mechanisms. In addition, we highlight the importance of molecular size/dimension regarding their profound impact on electrochemical performances. Finally, challenges and perspectives are discussed from the developing point of view for future AZIBs. We hope to provide a valuable evaluation on organic electrode materials for AZIBs in our context and give inspiration for the rational design of high-performance AZIBs.

Lama1 upregulation prolongs the lifespan of the dyH/dyH mouse model of LAMA2-related congenital muscular dystrophy.

LAMA2-related congenital muscular dystrophy (LAMA2-CMD), characterized by laminin-α2 deficiency, is debilitating and ultimately fatal. To date, no effective therapy has been clinically available. Laminin-α1, which shares significant similarities with laminin-α2, has been proven as a viable compensatory modifier. To evaluate its clinical applicability, we establish a Lama2 exon-3-deletion mouse model (dyH/dyH). The dyH/dyH mice exhibit early lethality and typical LAMA2-CMD phenotypes, allowing the evaluation of various endpoints. In dyH/dyH mice treated with synergistic activation mediator-based CRISPRa-mediated Lama1 upregulation, a nearly doubled median survival is observed, as well as improvements in weight and grip. Significant therapeutical effects are revealed by MRI, serum biochemical indices, and muscle pathology studies. Treating LAMA2-CMD with LAMA1 upregulation is feasible, and early intervention can alleviate symptoms and extend lifespan. Additionally, we reveal the limitations of LAMA1 upregulation, including high-dose mortality and non-sustained expression, which require further optimization in future studies.

Neutrophil Extracellular Traps in Breast Cancer: Roles in Metastasis and Beyond.

Despite advances in the treatment of breast cancer, the disease continues to exhibit high global morbidity and mortality. The importance of neutrophils in cancer development has been increasingly recognized. Neutrophil extracellular traps (NETs) are web-like structures released into the extracellular space by activated neutrophils, serving as a potential antimicrobial mechanism for capturing and eliminating microorganisms. The roles played by NETs in cancer development have been a subject of intense research in the last decade. In breast cancer, current evidence suggests that NETs are involved in various stages of cancer development, particularly during metastasis. In this review, we try to provide an updated overview of the roles played by NETs in breast cancer metastasis. These include: 1) facilitating systemic dissemination of cancer cells; 2) promoting cancer-associated inflammation; 3) facilitating cancer-associated thrombosis; 4) facilitating pre-metastatic niche formation; and 5) awakening dormant cancer cells. The translational implications of NETs in breast cancer treatment are also discussed. Understanding the relationship between NETs and breast cancer metastasis is expected to provide important insights for developing new therapeutic strategies for breast cancer patients.

Mixed methods examination of risk perception on vaccination intentions: The perspective of doctor-patient communication.

AIM: From the perspective of doctor-patient communication, this research used multiple methods combined natural language processing (NLP), a cross-sectional survey and an online experiment to investigated how risk perception influenced people's vaccination intention. METHODS: In Study 1, we used Python to crawl 335,045 comments about COVID-19 vaccine published in a social media platform Sina Weibo (equivalent of Twitter in China) from 31 December 2020 to 31 December 2021. Text analysis and sentiment analysis was used to examine how vaccination intention, as measured by linguistic features from the LIWC dictionary, changed with individuals' perceptions of pandemic risk. In Study 2, we adopted a cross-sectional questionnaire survey to further test the relation of risk perception, vaccination intention, trust in physicians, and perceived medical recommendations in a Chinese sample (n = 386). In Study 3, we conducted an online experiment where we recruited 127 participants with high trust in physicians and 127 participants with low trust, and subsequently randomly allocated them into one of three conditions: control, rational recommendation, or perceptual recommendation. RESULTS: Text and sentiment analysis revealed that the use of negative words towards COVID-19 vaccine had a significant decrease at high (vs. low) risk perception level time (Study 1). Trust in physicians mediated the effect of risk perception on vaccination intention and this effect was reinforced for participants with low (vs. high) level of perceived medical recommendation (Study 2), especially for the rational (vs. perceptual) recommendation condition (Study 3). CONCLUSION: Risk perception increased vaccination intention through the mediating effect of trust in physicians and the moderating effect of perceived medical recommendations. Rational (vs. perceptual) recommendation is more effective in increasing intention to get vaccinated in people with low trust in physicians.

Electropolymerization of Donor-Acceptor Conjugated Polymer for Efficient Dual-Ion Storage.

Rationally designed organic redox-active materials have attracted numerous interests due to their excellent electrochemical performance and reasonable sustainability. However, they often suffer from poor cycling stability, intrinsic low operating potential, and poor rate performance. Herein, a novel Donor-Acceptor (D-A) bipolar polymer with n-type pyrene-4,5,9,10-tetraone unit storing Li cations and p-type carbazole unit which attracts anions and provides polymerization sites is employed as a cathode for lithium-ion batteries through in situ electropolymerization. The multiple redox reactions and boosted kinetics by the D-A structure lead to excellent electrochemical performance of a high discharge capacity of 202 mA h g-1 at 200 mA g-1, impressive working potential (2.87 and 4.15 V), an outstanding rate capability of 119 mA h g-1 at 10 A g-1 and a noteworthy energy density up to 554 Wh kg-1. This strategy has significant implications for the molecule design of bipolar organic cathode for high cycling stability and high energy density.

Ambient and focal attention during complex problem-solving: preliminary evidence from real-world eye movement data.

Time course analysis of eye movements during free exploration of real-world scenes often reveals an increase in fixation durations together with a decrease in saccade amplitudes, which has been explained within the two visual systems approach, i.e., a transition from ambient to focal. Short fixations and long saccades during early viewing periods are classified as ambient mode of vision, which is concerned with spatial orientation and is related to simple visual properties such as motion, contrast, and location. Longer fixations and shorter saccades during later viewing periods are classified as focal mode of vision, which is concentrated in the foveal projection and is capable of object identification and its semantic categorization. While these findings are mainly obtained in the context of image exploration, the present study endeavors to investigate whether the same pattern of interplay between ambient and focal visual attention is deployed when people work on complex real-world tasks-and if so, when? Based on a re-analysis of existing data that integrates concurrent think aloud and eye tracking protocols, the present study correlated participants' internal thinking models to the parameters of their eye movements when they planned solutions to an open-ended design problem in a real-world setting. We hypothesize that switching between ambient and focal attentional processing is useful when solvers encounter difficulty compelling them to shift their conceptual direction to adjust the solution path. Individuals may prefer different attentional strategies for information-seeking behavior, such as ambient-to-focal or focal-to-ambient. The observed increase in fixation durations and decrease in saccade amplitudes during the periods around shifts in conceptual direction lends support to the postulation of the ambient-to-focal processing; however, focal-to-ambient processing is not evident. Furthermore, our data demonstrate that the beginning of a shift in conceptual direction is observable in eye movement behavior with a significant prolongation of fixation. Our findings add to the conclusions drawn from laboratory settings by providing preliminary evidence for ambient and focal processing characteristics in real-world problem-solving.

Release of biogenic volatile organic compounds and physiological responses of two sub-tropical tree species to smoke derived from forest fire.

Forests emit a large amount of biogenic volatile organic compounds (BVOCs) in response to biotic and abiotic stress. Despite frequent occurrence of large forest fires in recent years, the impact of smoke stress derived from these forest fires on the emission of BVOCs is largely unexplored. Thus, the aims of the study were to quantify the amount and composition of BVOCs released by two sub-tropical tree species, Cunninghamia lanceolata and Schima superba, in response to exposure to smoke. Physiological responses and their relationship with BVOCs were also investigated. The results showed that smoke treatments significantly (p < 0.001) promoted short-term release of BVOCs by C. lanceolata leaves than S. superba; and alkanes, olefins and benzene homologs were identified as major classes of BVOCs. Both C. lanceolata and S. superba seedlings showed significant (p < 0.005) physiological responses after being smoke-stressed where photosynthetic rate remained unaffected, chlorophyll content greatly reduced and Activities of anti-oxidant enzymes and the malondialdehyde content generally increased with the increase in smoke concentration. Activities of anti-oxidant enzymes showed mainly positive correlations with the major BVOCs. In conclusion, the release of BVOCs following smoke stress is species-specific and there exists a link between activities of antioxidant enzymes and BVOCs released. The findings provide insight about management of forest fires in order to control excessive emission of smoke that would trigger increased release of BVOCs.

Adenine base editor-based correction of the cardiac pathogenic Lmna c.1621C > T mutation in murine hearts.

Base editors are emerging as powerful tools to correct single-nucleotide variants and treat genetic diseases. In particular, the adenine base editors (ABEs) exhibit robust and accurate adenine-to-guanidine editing capacity and have entered the clinical stage for cardiovascular therapy. Despite the tremendous progress using ABEs to treat heart diseases, a standard technical route toward successful ABE-based therapy remains to be fully established. In this study, we harnessed adeno-associated virus (AAV) and a mouse model carrying the cardiomyopathy-causing Lmna c.1621C > T mutation to demonstrate key steps and concerns in designing a cardiac ABE experiment in vivo. We found DeepABE as a reliable deep-learning-based model to predict ABE editing outcomes in the heart. Screening of sgRNAs for a Cas9 mutant with relieved protospacer adjacent motif (PAM) allowed the reduction of bystander editing. The ABE editing efficiency can be significantly enhanced by modifying the TadA and Cas9 variants, which are core components of ABEs. The ABE systems can be delivered into the heart via either dual AAV or all-in-one AAV vectors. Together, this study showcased crucial technical considerations in designing an ABE system for the heart and pointed out major challenges in further improvement of this new technology for gene therapy.

Periodontium-Mimicking, Multifunctional Biomass-Based Hydrogel Promotes Full-Course Socket Healing.

Preserving stable tooth-periodontal tissue integration is vital for maintaining alveolar bone stability under physiological conditions. However, tooth extraction compromises this integration and impedes socket healing. Therefore, it becomes crucial to provide early stage coverage of the socket to promote optimal healing. Drawing inspiration from the periodontium, we have developed a quaternized methacryloyl chitosan/dopamine-grafted oxidized sodium alginate hydrogel, termed the quaternized methacryloyl chitosan/dopamine-grafted oxidized sodium alginate hydrogel (QDL hydrogel). Through blue-light-induced cross-linking, the QDL hydrogel serves as a comprehensive wound dressing for socket healing. The QDL hydrogel exhibits remarkable efficacy in closing irregular tooth extraction wounds. Its favorable mechanical properties, flexible formability, and strong adhesion are achieved through modifications of chitosan and sodium alginate derived from biomass sources. Moreover, the QDL hydrogel demonstrates a superior hemostatic ability, facilitating swift blood clot formation. Additionally, the inherent antibacterial properties of the QDL hydrogel effectively inhibit oral microorganisms. Furthermore, the QDL hydrogel promotes angiogenesis, which facilitates the nutrient supply for subsequent tissue regeneration. Notably, the hydrogel accelerates socket healing by upregulating the expression of genes associated with wound healing. In conclusion, the periodontium-mimicking multifunctional hydrogel exhibits significant potential as a clinical tooth extraction wound dressing.

DNA Hypomethylation-Mediated Transcription Dysregulation Participates in Pathogenesis of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a highly heterogeneous and genetically complex endocrine disorder. Although the etiology remains mostly elusive, growing evidence suggests that abnormal changes of DNA methylation correlate well with systemic and tissue-specific dysfunctions in PCOS. Herein, a dehydroepiandrosterone-induced PCOS-like mouse model which has a similar metabolic and reproductive phenotype as human patients with PCOS was generated. It was used to experimentally validate the potential role of aberrant DNA methylation in PCOS in this study. Integrated DNA methylation and transcriptome analysis revealed the potential role of genomic DNA hypomethylation in transcription regulation of PCOS and identified several key candidate genes, including BMP4, Adcy7, Tnfaip3, and Fas, which were regulated by aberrant DNA hypomethylation. Moreover, i.p. injection of S-adenosylmethionine increased the overall DNA methylation level of PCOS-like mice and restored expression of the candidate genes to similar levels as the control, alleviating reproductive and metabolic abnormalities in PCOS-like mice. These findings provide direct evidence showing the importance of normal DNA methylation in epigenetic regulation of PCOS and potential targets for diagnosis and treatment of the disease.