The scaffolding function of LSD1 controls DNA methylation in mouse ESCs.

Lysine-specific histone demethylase 1 (LSD1), which demethylates mono- or di- methylated histone H3 on lysine 4 (H3K4me1/2), is essential for early embryogenesis and development. Here we show that LSD1 is dispensable for mouse embryonic stem cell (ESC) self-renewal but is required for mouse ESC growth and differentiation. Reintroduction of a catalytically-impaired LSD1 (LSD1MUT) recovers the proliferation capability of mouse ESCs, yet the enzymatic activity of LSD1 is essential to ensure proper differentiation. Indeed, increased H3K4me1 in Lsd1 knockout (KO) mouse ESCs does not lead to major changes in global gene expression programs related to stemness. However, ablation of LSD1 but not LSD1MUT results in decreased DNMT1 and UHRF1 proteins coupled to global hypomethylation. We show that both LSD1 and LSD1MUT control protein stability of UHRF1 and DNMT1 through interaction with HDAC1 and the ubiquitin-specific peptidase 7 (USP7), consequently, facilitating the deacetylation and deubiquitination of DNMT1 and UHRF1. Our studies elucidate a mechanism by which LSD1 controls DNA methylation in mouse ESCs, independently of its lysine demethylase activity.

Improved microbial-plant soil bioremediation of PAHs and heavy metal through in silico methods.

The combined pollution of polycyclic aromatic hydrocarbons (PAHs) and organic cadmium (Cd) in farmland soils, and the field controlling strategy need to be studied urgently. In this study, 5 PAHs, 5 Cd and 11 soil conditioners were selected to explore the co-exposure risk and remediation efficiency. Firstly, a significant combination Fl-alkylalkoxy cadmium was obtained using forward and reverse methods coupling variation coefficient methods (the combined pollution value was 0.173). Secondly, the interaction energy of microbial degradation / plant absorption of Fl under Cd stress, and microbial mineralization / plant absorption of alkylalkoxy cadmium under PAHs stress were characterized using factorial experimental design, molecular docking and molecular dynamics simulation. The combined pollution of alkylalkoxy cadmium and dialkyl cadmium, phenanthrene and Benzo [a] pyrene was significant (synergistic contribution rates were 17.58 % and 19.22 %, respectively). In addition, 6 soil conditioners with significant efficiency were selected to design Taguchi orthogonal experimental schemes, indicating the microbial degradation / mineralization and plant absorption were significantly effective (the maximum increase of remediation efficiency was 93.81 %) under the combinations (i.e., trratone, coumarol, fulvamic acid, potassium fertilizer and others, etc.). Finally, it was found that the soil conditioners affected the hydrophobic groups and forces, and the efficiency was proportional to the highest peak value and minimum distance in the RDF curve. This study identifies the risk characteristics of co-exposure of PAHs and Cd and screens effective soil conditioners, providing theoretical guidance for risk controlling.

Roles of exosomes in immunotherapy for solid cancers.

Although immunotherapy has made breakthrough progress, its efficacy in solid tumours remains unsatisfactory. Exosomes are the main type of extracellular vesicles that can deliver various intracellular molecules to adjacent or distant cells and organs, mediating various biological functions. Studies have found that exosomes can both activate the immune system and inhibit the immune system. The antigen and major histocompatibility complex (MHC) carried in exosomes make it possible to develop them as anticancer vaccines. Exosomes derived from blood, urine, saliva and cerebrospinal fluid can be used as ideal biomarkers in cancer diagnosis and prognosis. In recent years, exosome-based therapy has made great progress in the fields of drug transportation and immunotherapy. Here, we review the composition and sources of exosomes in the solid cancer immune microenvironment and further elaborate on the potential mechanisms and pathways by which exosomes influence immunotherapy for solid cancers. Moreover, we summarize the potential clinical application prospects of engineered exosomes and exosome vaccines in immunotherapy for solid cancers. Eventually, these findings may open up avenues for determining the potential of exosomes for diagnosis, treatment, and prognosis in solid cancer immunotherapy.

Reduction strategies of polycyclic aromatic hydrocarbons in farmland soils: Microbial degradation, plant transport inhibition, and their mechanistic analysis.

This study focuses on the abatement of polycyclic aromatic hydrocarbons (PAHs), a global pollutant, in farmland soils. Seven controlled PAHs in China were used as the target ligands, and four key target receptors degradable PAHs and two key target receptors transport PAHs were used as the target receptors. Firstly, the degradation abilities of the four key target receptors on PAHs were quantified, and the dominant target receptors that could efficiently degrade PAHs were screened out. Then, the co-degradation abilities of PAHs under the coexistence of the dominant target receptors (microbial diversity) were assessed, and 30 external condition-adding schemes to promote the microbial (co-)degradation of PAHs were designed. In addition, the microbial dominant target receptor mutants and the plant key target receptor mutants were obtained, the degradation and transportation of PAHs were improved by 8.06%∼22.27% and 39.86%∼45.43%. Finally, the mechanism analysis of PAHs biodegradation and transportation found that the Van der Waals interactions dominated the enhancement of PAHs' degradation in soil, and the solvation capacity dominated the decrease of PAHs' transportation in plant. This study aims to provide theoretical support for the prevention and control of PAHs residue pollution in farmland soil, as well as the protection of human dietary health.

ZFP281 controls transcriptional and epigenetic changes promoting mouse pluripotent state transitions via DNMT3 and TET1.

The progression from naive through formative to primed in vitro pluripotent stem cell states recapitulates epiblast development in vivo during the peri-implantation period of mouse embryo development. Activation of the de novo DNA methyltransferases and reorganization of transcriptional and epigenetic landscapes are key events that occur during these pluripotent state transitions. However, the upstream regulators that coordinate these events are relatively underexplored. Here, using Zfp281 knockout mouse and degron knockin cell models, we identify the direct transcriptional activation of Dnmt3a/3b by ZFP281 in pluripotent stem cells. Chromatin co-occupancy of ZFP281 and DNA hydroxylase TET1, which is dependent on the formation of R-loops in ZFP281-targeted gene promoters, undergoes a "high-low-high" bimodal pattern regulating dynamic DNA methylation and gene expression during the naive-formative-primed transitions. ZFP281 also safeguards DNA methylation in maintaining primed pluripotency. Our study demonstrates a previously unappreciated role for ZFP281 in coordinating DNMT3A/3B and TET1 functions to promote pluripotent state transitions.

The heat is on: Consumers modify their oral processing behavior when eating spicy foods.

Food texture properties and consumer characteristics influence oral processing behaviors. Little is known about oral processing behavior of pungent spicy foods. In two experiments, we investigated how adding ground dried chilies to tomato soup or beef patties and curried rice altered oral processing behaviors. In Experiment One, tomato soups differing in concentration of added ground dried chilies (0.01, 0.03, 0.20 or 0.40% w/w) were consumed (n = 23). In Experiment Two, lunch meals that differed in added ground dried chilies consisting of beef patties (0.0, 0.6 or 1.2% w/w) and curried rice (0.0, 0.4 or 1.0% w/w) were consumed (n = 49). Sip/bite sizes were determined using hidden balances. Oral processing behavior was quantified using video recordings followed by post hoc annotations of specific behaviors. When eating tomato soup, increasing oral burn was associated with increasing number of water sips, water intake and total time between sips. For the solid meals (beef patties and curried rice), increasing oral burn was associated with increased time between bites and total sips of water; conversely, total oral exposure time, total number of chews and number of chews per bite all decreased with greater burn. Saliva content and rate of saliva incorporation into the solid food bolus increased with added ground dried chilies while oral exposure time decreased. We conclude consumers adapt their oral processing behaviors to oral burn of solid foods by reducing oro-sensory exposure time, chewing bites less, increasing time between bites, and consuming more water, potentially to mitigate the discomfort associated with the burn imparted by ground dried chilies.

CoOOH with a highly negative CB band for visible-light-driven photocatalytic degradation of refractory organic pollutants in peroxymonosulfate system: Enhanced performance and multi-path synergetic mechanisms.

To date, cobalt ions/oxides were proven to be the best peroxymonosulfate (PMS) activator in the homogeneous/heterogeneous system. Interestingly, we found out that CoOOH with a narrow band gap (2.18 eV) and highly negative CB band (-1.73 eV) showed a good potential to be a visible-light-driven photocatalyst for PMS activation. The results turned out that the reaction rate constant of typical refractory contaminants in the Vis-CoOOH/PMS system was about 2-5 times higher than that in the Dark-CoOOH/PMS system. The photogenerated electron (e-) and hole (h+) can react with PMS, which significantly facilitates charge separation. Meanwhile, the e- on the highly negative CB band can react with oxygen to generate O2•-, which simultaneously accelerates the cycle Co(III)/Co(II) to generate radicals (O2•-, •OH and SO4•-) and non-radical (1O2). As a result, multiple ROS was involved in the degradation of contaminants. Especially, O2•- with a longer half-life over 1O2 is identified as the dominant ROS, enhancing the utilization of radicals and the effective attack with contaminants. Therefore, this study first reports the great potential of CoOOH as a visible-light photocatalyst and reveals the multi-path mechanism of the synergistic visible-light-driven photocatalysis and PMS activation for removing refractory contaminants in wastewater.

Field measures of strengthen plant-microbial remediation of PAHs-FQs compound pollution.

In this study, five PAHs (benzo [b] fluoranthene (BbF), phenanthrene (Phe), fluoranthene (Flu), fluorene (Fl), benzo [A] pyrene (Bap)), and five FQs (ofloxacin (OFL), enrofloxacin (ENR), ciprofloxacin (CIP), norfloxacin (NOR), lomefloxacin (LOM)) were selected as ligands; peroxidase (1NML) was selected as receptor degrading protein. In the plant-microbial degradation, the factors with significant inhibitory effects are NOR, Bap, CIP, ENR, OFL, Flu, LOM, Phe, Fl, and BbF by the fractional factorial design experiment and molecular docking-assisted molecular dynamics methods. Using Taguchi experiment and molecular dynamics simulation methods, the main external field measures were designed and screened to effectively promote the degradation of PAHs-FQs under the combined pollution scenarios of Bap-CIP and BbF-NOR, respectively. The peroxidase mutation design plans with enhanced substrate affinity were then designed and screened using the DS software by predicting the virtual key amino acid of peroxidase. The novel biodegradable enzymes 2YCD-1, 2YCD-4, 2YCD-5, 2YCD-7, and 2YCD-9 had better structures and showed excellent degradability for PAHs and FQs. This study explored the degradation rules of the composite pollutants in the coexistence systems of multiple PAHs and FQs, providing the best external field measures for the control and treatment of the combined pollution effects of different PAHs and FQs. Overall, the current study has important practical significance for promoting the plant-microbial joint remediation of PAHs-FQs pollution and for reducing the combined pollution of PAHs and FQs in farmland systems.

ZFP281 coordinates DNMT3 and TET1 for transcriptional and epigenetic control in pluripotent state transitions.

The progression from naive through formative to primed in vitro pluripotent stem cell states recapitulates the development of the epiblast in vivo during the peri-implantation period of mammalian development. Activation of the de novo DNA methyltransferases and reorganization of transcriptional and epigenetic landscapes are key events occurring during these pluripotent state transitions. However, the upstream regulators that coordinate these events are relatively underexplored. Here, using Zfp281 knockout mouse and degron knock-in cell models, we uncover the direct transcriptional activation of Dnmt3a/3b by ZFP281 in pluripotent stem cells. Chromatin co-occupancy of ZFP281 and DNA hydroxylase TET1, dependent on the formation of R loops in ZFP281-targeted gene promoters, undergoes a "high-low-high" bimodal pattern regulating dynamic DNA methylation and gene expression during the naïive-formative-primed transitions. ZFP281 also safeguards DNA methylation in maintaining primed pluripotency. Our study demonstrates a previously unappreciated role for ZFP281 in coordinating DNMT3A/3B and TET1 functions to promote pluripotent state transitions.

Identification and quantification of DNA N6-methyladenine modification in mammals: A challenge to modern analytical technologies.

DNA N6-methyladenine modification (6mA) is a predominant epigenetic mark in prokaryotes but rarely present in multicellular metazoa. The analytical technologies have been developed for sensitive detection of 6mA, including ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS) and single molecule real-time sequencing (SMRTseq). However, it remains challenging to detect 6mA at global level and/or in the context of sequence in multicellular metazoa (including mammals). This mini-review brings insights into current dilemma and potential solutions for the identification and quantifications of 6mA in mammals.

Quantitatively regulating the ketone structure of triazine-based covalent organic frameworks for efficient visible-light photocatalytic degradation of organic pollutants: Tunable performance and mechanisms.

As promising visible-light-responsive photocatalysts, triazine-based covalent organic frameworks (CTFs) still suffer from broad bandgap and high electron-hole recombination. As such, different contents of electron-rich ketone group were introduced to CTFs (X % keto-CTF), aiming to clarify the mechanism of quantitatively regulating ketone for enhanced visible-light photocatalytic performance of CTFs. As ketone content increased, the bandgap narrowed, electron-hole recombination decreased, charge transfer and quantum yield increased. As a result, keto-CTF outperformed other keto-CTFs in visible-light photocatalytic degradation of tetracycline, and apparent rate constant of TC (kobs) was 3.69 times higher than that of CTF. Importantly, ketone tuning induced varied types and concentrations of reactive species. Integrated with quantitative structure-activity relationships (QSARs) analysis and density functional theory (DFT) calculations, this study unravels how ketone content regulates bandgap structure of CTF, affects the contribution of varied reactive species, and quantitatively enhances the photocatalytic performance of CTFs. It also provides novel insights into the precise design and synthesis of CTFs-based catalyst structures for high-efficient visible-light photocatalytic degradation of organic pollutants.

Getting hot: Effect of chili pepper addition on sensory perception of liquid and solid foods.

The impact of trigeminal oral burn and pungency on taste, flavor, and mouth-feel perception of commercially available foods is underexplored. This study aimed to determine the effect of oral burn sensations evoked by the addition of chili powder to tomato soup, beef burger patties, and curried rice on taste, flavor, and mouth-feel perception. Chili powder was added to tomato soups, beef burger patties, and curried rice at four concentrations. A consumer panel comprising n = 66 participants (49 women, 25.5 ± 5.8 years, BMI 22.9 ± 2.8 kg/m2 ) assessed taste, flavor, trigeminal, and mouth-feel intensity of all samples using Rate-All-That-Apply methodology. Food matrix consistency strongly impacted oral burn sensations with solid food matrices (beef burger patties and curried rice) suppressing oral burn intensity compared to liquid food matrices (tomato soup). With increasing oral burn intensity, perceived intensity of beef flavor decreased significantly for beef burger patties. Tomato flavor, sweetness, and sourness intensity decreased significantly with increasing oral burn intensity for tomato soups. Perceived burn intensity of all food matrices and beef flavor intensity of beef burger patties differed between infrequent and frequent chili pepper consumers. We conclude that increasing oral burn intensity by the addition of chili pepper powder led to only small reductions in taste and flavor intensity of tomato soups and to little or no changes in flavor and mouth-feel perception of beef burger patties and curried rice. We suggest that reductions in taste, flavor, and mouth-feel intensity caused by oral burn might be more pronounced in liquid (tomato soup) than solid foods (beef burger patties and curried rice). PRACTICAL APPLICATION: There is a growing public and scientific interest in the development of strategies to increase the sensory appeal of healthy foods and beverages. Incorporation of trigeminal stimuli, such as chili peppers or capsaicin (pungent component of chili peppers), can be a strategy to increase sensory appeal of foods and beverages. Little is known about how trigeminal oral burn and pungency influence taste, flavor, and mouth-feel perception of commercially available foods, although it has been well established that taste, flavor, mouth-feel, and trigeminal sensations contribute to product acceptance. By investigating the sensory impact of oral burn on flavor and mouth-feel perception of foods, this study may help to better understand how trigeminal stimuli can be applied to moderate flavor and mouth-feel perception of foods to optimize sensory appeal.

Potential Toxicity Risk Assessment and Priority Control Strategy for PAHs Metabolism and Transformation Behaviors in the Environment.

In this study, 16 PAHs were selected as the priority control pollutants to summarize their environmental metabolism and transformation processes, including photolysis, plant degradation, bacterial degradation, fungal degradation, microalgae degradation, and human metabolic transformation. Meanwhile, a total of 473 PAHs by-products generated during their transformation and degradation in different environmental media were considered. Then, a comprehensive system was established for evaluating the PAHs by-products' neurotoxicity, immunotoxicity, phytotoxicity, developmental toxicity, genotoxicity, carcinogenicity, and endocrine-disrupting effect through molecular docking, molecular dynamics simulation, 3D-QSAR model, TOPKAT method, and VEGA platform. Finally, the potential environmental risk (phytotoxicity) and human health risks (neurotoxicity, immunotoxicity, genotoxicity, carcinogenicity, developmental toxicity, and endocrine-disrupting toxicity) during PAHs metabolism and transformation were comprehensively evaluated. Among the 473 PAH's metabolized and transformed products, all PAHs by-products excluding ACY, CHR, and DahA had higher neurotoxicity, 152 PAHs by-products had higher immunotoxicity, and 222 PAHs by-products had higher phytotoxicity than their precursors during biological metabolism and environmental transformation. Based on the TOPKAT model, 152 PAH by-products possessed potential developmental toxicity, and 138 PAH by-products had higher genotoxicity than their precursors. VEGA predicted that 247 kinds of PAH derivatives had carcinogenic activity, and only the natural transformation products of ACY did not have carcinogenicity. In addition to ACY, 15 PAHs produced 123 endocrine-disrupting substances during metabolism and transformation. Finally, the potential environmental and human health risks of PAHs metabolism and transformation products were evaluated using metabolic and transformation pathway probability and degree of toxic risk as indicators. Accordingly, the priority control strategy for PAHs was constructed based on the risk entropy method by screening the priority control pathways. This paper assesses the potential human health and environmental risks of PAHs in different environmental media with the help of models and toxicological modules for the toxicity prediction of PAHs by-products, and thus designs a risk priority control evaluation system for PAHs.

A TET1-PSPC1-Neat1 molecular axis modulates PRC2 functions in controlling stem cell bivalency.

TET1 maintains hypomethylation at bivalent promoters through its catalytic activity in embryonic stem cells (ESCs). However, TET1 catalytic activity-independent function in regulating bivalent genes is not well understood. Using a proteomics approach, we map the TET1 interactome in ESCs and identify PSPC1 as a TET1 partner. Genome-wide location analysis reveals that PSPC1 functionally associates with TET1 and Polycomb repressive complex-2 (PRC2). We establish that PSPC1 and TET1 repress, and the lncRNA Neat1 activates, bivalent gene expression. In ESCs, Neat1 is preferentially bound to PSPC1 alongside its PRC2 association at bivalent promoters. During the ESC-to-epiblast-like stem cell (EpiLC) transition, PSPC1 and TET1 maintain PRC2 chromatin occupancy at bivalent gene promoters, while Neat1 facilitates the activation of certain bivalent genes by promoting PRC2 binding to their mRNAs. Our study demonstrates a TET1-PSPC1-Neat1 molecular axis that modulates PRC2-binding affinity to chromatin and bivalent gene transcripts in controlling stem cell bivalency.

Rare and misincorporated DNA N6-methyladenine is a hallmark of cytotoxic stresses for selectively stimulating the stemness and proliferation of glioblastoma cells.

The entity of DNA N6-methyladenine (6mA) in mammals remains elusive and subsequently its roles in diseases are poorly understood. Here we exploited a bacterial DNA contamination-free and ultrasensitive UHPLC-MS/MS assay to reassess DNA 6mA in human glioblastomas and unveiled that DNA 6mA (~0.08 ppm) is extremely rare. By the use of two independent heavy stable isotope-labeling strategies, we further prove that the observed 6mA is solely generated by DNA polymerase-mediated misinocorporation. In vitro experiments point toward that the generation of misincorporated DNA 6mA is associated with the cellular stresses-caused release of RNA N6-methyladenine (m6A) nucleoside, which is profoundly inhibited by hypoxia milieu. Consistently, compared with normal brain tissues, DNA 6mA decreases in hypoxic human gliomas. Our data also strongly support that rare DNA 6mA rather than relatively abundant DNA 5-methylcytosine and 5-hydroxymethylcytosine is a hallmark of poor prognosis of IDH1/2 mutation-absent glioblastoma patients, reflecting the incidence of cytotoxic stresses and subsequent release of m6A nucleoside. The released m6A nucleoside may selectively preserve a subset of the glioblastoma cells and stimulate their stemness and proliferation. Noteworthily, demethylation-inhibiting IDH1 mutation increases the DNA 6mA content in human gliomas, but the depletion of the demethylase candidate ALKBH1 fails to do so, together suggesting the presence of other unknown 6mA demethylase for erasing misincorporated DNA 6mA. This is the first report on the identification of the misincorporated 6mA together with its origin and roles in diseases.

Capsaicin burn increases thickness discrimination thresholds independently of chronic chili intake.

The trigeminal nerve transduces both chemical irritation and textural sensations suggesting that perception in one may influence perception in the other. Little is known about how the oral burn of capsaicin may affect texture sensitivity. The aim of this study was to determine the effect of burning sensations on thickness discrimination thresholds in liquid foods assessed by consumers who vary in habitual spicy food intake. Forty-seven Caucasian participants (31 females and 16 males; mean age: 25.0 ± 5.7 yrs; mean BMI: 21.5 ± 2.6 kg/m2) were recruited in the Netherlands. Chili pepper intake frequency and preference for chili peppers and spicy foods were assessed using questionnaires. Perceived burn and disliking/liking of bouillon soups thickened with xanthan gum (concentrations ranging from 0.06 to 0.21 g/mL; viscosity at 50 s-1 (η50s-1) ranging from 11 to 48 mPas) containing varying amounts of capsaicin (0, 1, or 10 ppm) were determined using generalized scales (gLMS and gDOL). Estimates of thickness discrimination thresholds were determined using the 2-Alternative Forced Choice ascending staircase method. Capsaicin was applied in two ways: (i) capsaicin was added directly to the soups or (ii) a pre-rinse of a capsaicin solution was held in mouth before evaluating soups without capsaicin. As expected, frequent chili pepper consumers reported significantly lower burn intensity and higher hedonic ratings compared to infrequent consumers. Thickness discrimination thresholds (i.e., BET expressed as Δη50s-1) increased significantly from 11.3 mPas at 0 ppm to 16.1 mPas at 1 ppm (42% increase) to 21.4 mPas at 10 ppm capsaicin (89% increase) on average across all participants. Similar modification of thickness discrimination thresholds were observed regardless of whether capsaicin was added to the soup or was applied as a pre-rinse. No significant differences in thickness discrimination thresholds were observed between infrequent and frequent chili consumers. We conclude that oral burn caused by capsaicin affects thickness discrimination independently of reported chili pepper intake. Also, we suggest the ability of capsaicin to alter thickness discrimination may be due to increased neural noise, attentional effects or cross-modal interactions.

A novel MnOOH coated nylon membrane for efficient removal of 2,4-dichlorophenol through peroxymonosulfate activation.

2,4-Dichlorophenol (2,4-DCP) is a highly toxic water contaminant. In this study, we demonstrate a novel catalytic filtration membrane by coating MnOOH nanoparticles on nylon membrane (MnOOH@nylon) for improved removal of 2,4-DCP through a synergetic "trap-and-zap" process. In this hybrid membrane, the underlying nylon membrane provides high adsorption affinity for 2,4-DCP. While the immobilized MnOOH nanoparticles on the membrane surface provide catalytic property for peroxymonosulfate activation to produce reactive oxygen species (ROS), which migrate with the fluid to the underlying nylon membrane pore channels and react with the adsorbed 2,4-DCP with a much higher rate (0.9575 mg L-1 min-1) than that in the suspended MnOOH particle system (0.1493 mg L-1 min-1). The forced flow in the small voids of the MnOOH nanoparticle coating layer (< 200 nm) and channels of nylon membrane (~220 nm) is critical to improve the 2,4-DCP adsorption, ROS production, and 2,4-DCP degradation. The hybrid MnOOH@nylon membrane also improves the stability of the MnOOH nanoparticles and the resistibility to competitive anions, due to much higher concentration ratio of the adsorbed 2,4-DCP and produced ROS versus background competitive ions in the membrane phase. This study provides a generally applicable approach to achieve high removal of target contaminants in catalytic membrane processes.

USP7 negatively controls global DNA methylation by attenuating ubiquitinated histone-dependent DNMT1 recruitment.

Previous studies have implicated an essential role for UHRF1-mediated histone H3 ubiquitination in recruiting DNMT1 to replication sites for DNA maintenance methylation during S phase of the cell cycle. However, the regulatory mechanism on UHRF1-mediated histone ubiquitination is not clear. Here we present evidence that UHRF1 and USP7 oppositely control ubiquitination of histones H3 and H2B in S phase of the cell cycle and that DNMT1 binds both ubiquitinated H3 and H2B. USP7 knockout markedly increased the levels of ubiquitinated H3 and H2B in S phase, the association of DNMT1 with replication sites and importantly, led to a progressive increase of global DNA methylation shown with increased cell passages. Using DNMT3A/DNMT3B/USP7 triple knockout cells and various DNA methylation analyses, we demonstrated that USP7 knockout led to an overall elevation of DNA methylation levels. Mechanistic study demonstrated that USP7 suppresses DNMT1 recruitment and DNA methylation through its deubiquitinase activity and the interaction with DNMT1. Altogether our study provides evidence that USP7 is a negative regulator of global DNA methylation and that USP7 protects the genome from excessive DNA methylation by attenuating histone ubiquitination-dependent DNMT1 recruitment.