The landscape of RNA Pol II binding reveals a stepwise transition during ZGA.

Zygotic genome activation (ZGA) is the first transcription event in life1. However, it is unclear how RNA polymerase is engaged in initiating ZGA in mammals. Here, by developing small-scale Tn5-assisted chromatin cleavage with sequencing (Stacc-seq), we investigated the landscapes of RNA polymerase II (Pol II) binding in mouse embryos. We found that Pol II undergoes 'loading', 'pre-configuration', and 'production' during the transition from minor ZGA to major ZGA. After fertilization, Pol II is preferentially loaded to CG-rich promoters and accessible distal regions in one-cell embryos (loading), in part shaped by the inherited parental epigenome. Pol II then initiates relocation to future gene targets before genome activation (pre-configuration), where it later engages in full transcription elongation upon major ZGA (production). Pol II also maintains low poising at inactive promoters after major ZGA until the blastocyst stage, coinciding with the loss of promoter epigenetic silencing factors. Notably, inhibition of minor ZGA impairs the Pol II pre-configuration and embryonic development, accompanied by aberrant retention of Pol II and ectopic expression of one-cell targets upon major ZGA. Hence, stepwise transition of Pol II occurs when mammalian life begins, and minor ZGA has a key role in the pre-configuration of transcription machinery and chromatin for genome activation.

Trapping Layers Prevent Dopant Segregation and Enable Remote Doping of Templated Self-Assembled InGaAs Nanowires.

Selective area epitaxy is a promising approach to define nanowire networks for topological quantum computing. However, it is challenging to concurrently engineer nanowire morphology, for carrier confinement, and precision doping, to tune carrier density. We report a strategy to promote Si dopant incorporation and suppress dopant diffusion in remote doped InGaAs nanowires templated by GaAs nanomembrane networks. Growth of a dilute AlGaAs layer following doping of the GaAs nanomembrane induces incorporation of Si that otherwise segregates to the growth surface, enabling precise control of the spacing between the Si donors and the undoped InGaAs channel; a simple model captures the influence of Al on the Si incorporation rate. Finite element modeling confirms that a high electron density is produced in the channel.

Detection of Be dopant pairing in VLS grown GaAs nanowires with twinning superlattices.

Control over the distribution of dopants in nanowires is essential for regulating their electronic properties, but perturbations in nanowire microstructure may affect doping. Conversely, dopants may be used to control nanowire microstructure including the generation of twinning superlattices (TSLs)-periodic arrays of twin planes. Here the spatial distribution of Be dopants in a GaAs nanowire with a TSL is investigated using atom probe tomography. Homogeneous dopant distributions in both the radial and axial directions are observed, indicating a decoupling of the dopant distribution from the nanowire microstructure. Although the dopant distribution is microscopically homogenous, radial distribution function analysis discovered that 1% of the Be atoms occur in substitutional-interstitial pairs. The pairing confirms theoretical predictions based on the low defect formation energy. These findings indicate that using dopants to engineer microstructure does not necessarily imply that the dopant distribution is non-uniform.

The loss-of-function mutation of CETP affects HDLc levels but not ApoA1 in patients with acute myocardial infarction.

BACKGROUND AND AIMS: Loss of the cholesteryl ester transfer protein (CETP) function affects HDLc levels, but its effects on major HDL protein component ApoA1 are not well understood in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: We investigated the effects of an East Asian loss-of-function variant (rs2303790; p.D442G) in CETP gene on HDLc and ApoA1 levels and its relationship with AMI. A total of 2327 AMI patients and 2615 age- and sex-matched controls from INTERHEART-China study were included. In controls, both levels of HDLc (1.24 vs. 1.04 mmol/L, P = 0.001) and ApoA1 (1.48 vs. 1.37 mmol/L, P = 0.042) were significantly higher in CETP variant G allele carriers compared to CETP wildtype D allele carriers. In AMI patients, levels of HDLc were significantly higher (1.14 vs. 1.01 mmol/L, P = 0.013) while levels of ApoA1 were not statistically difference (1.31 vs. 1.32 mmol/L, P = 0.468) in CETP variant group compared to CETP wildtype group. Moreover, CETP variant is associated with HDLc increase, but is not associated with AMI risk (P = 0.564), even after adjusting for age, sex, history of hypertension and diabetes, waist to hip ratio, smoking, total cholesterol, LDL cholesterol, triglycerides, physical activity, depression, alcohol, vegetables and fruit consumption. CONCLUSIONS: Loss of CETP function is associated with increased HDLc and ApoA1 levels in healthy subjects, and in AMI patients, it is associated with HDLc levels but not ApoA1 levels. The lack of association of CETP variant with AMI may be related to the inability to increase ApoA1 levels and warranted further studies.

Remote Doping of Scalable Nanowire Branches.

Selective-area epitaxy provides a path toward high crystal quality, scalable, complex nanowire networks. These high-quality networks could be used in topological quantum computing as well as in ultrafast photodetection schemes. Control of the carrier density and mean free path in these devices is key for all of these applications. Factors that affect the mean free path include scattering by surfaces, donors, defects, and impurities. Here, we demonstrate how to reduce donor scattering in InGaAs nanowire networks by adopting a remote-doping strategy. Low-temperature magnetotransport measurements indicate weak anti-localization-a signature of strong spin-orbit interaction-across a nanowire Y-junction. This work serves as a blueprint for achieving remotely doped, ultraclean, and scalable nanowire networks for quantum technologies.

Correlated Nanoscale Analysis of the Emission from Wurtzite versus Zincblende (In,Ga)As/GaAs Nanowire Core-Shell Quantum Wells.

While the properties of wurtzite GaAs have been extensively studied during the past decade, little is known about the influence of the crystal polytype on ternary (In,Ga)As quantum well structures. We address this question with a unique combination of correlated, spatially resolved measurement techniques on core-shell nanowires that contain extended segments of both the zincblende and wurtzite polytypes. Cathodoluminescence hyperspectral imaging reveals a blue-shift of the quantum well emission energy by 75 ± 15 meV in the wurtzite polytype segment. Nanoprobe X-ray diffraction and atom probe tomography enable k·p calculations for the specific sample geometry to reveal two comparable contributions to this shift. First, there is a 30% drop in In mole fraction going from the zincblende to the wurtzite segment. Second, the quantum well is under compressive strain, which has a much stronger impact on the hole ground state in the wurtzite than in the zincblende segment. Our results highlight the role of the crystal structure in tuning the emission of (In,Ga)As quantum wells and pave the way to exploit the possibilities of three-dimensional band gap engineering in core-shell nanowire heterostructures. At the same time, we have demonstrated an advanced characterization toolkit for the investigation of semiconductor nanostructures.

Benzophenone and Benzoylphloroglucinol Derivatives from Hypericum sampsonii with Anti-Inflammatory Mechanism of Otogirinin A.

Three new compounds, 4-geranyloxy-2-hydroxy-6-isoprenyloxybenzophenone (1), hypericumone A (2) and hypericumone B (3), were obtained from the aerial parts of Hypericum sampsonii, along with six known compounds (4-9). The structures of these compounds were determined through spectroscopic and MS analyses. Hypericumone A (2), sampsonione J (8) and otogirinin A (9) exhibited potent inhibition (IC50 values ≤ 40.32 µM) against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation. Otogirinin A (9) possessed the highest inhibitory effect on NO production with IC50 value of 32.87 ± 1.60 µM. The well-known proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α) was also inhibited by otogirinin A (9). Western blot results demonstrated that otogirinin A (9) downregulated the high expression of inducible nitric oxide synthase (iNOS). Further investigations on the mechanism showed that otogirinin A (9) blocked the phosphorylation of MAPK/JNK and IκBα, whereas it showed no effect on the phosphorylation of MAPKs/ERK and p38. In addition, otogirinin A (9) stimulated anti-inflammatory M2 phenotype by elevating the expression of arginase 1 and Krüppel-like factor 4 (KLF4). The above results suggested that otogirinin A (9) could be considered as potential compound for further development of NO production-targeted anti-inflammatory agent.

Evaluation of Antioxidant and Anti-α-glucosidase Activities of Various Solvent Extracts and Major Bioactive Components from the Seeds of Myristica fragrans.

Myristica fragrans is a well-known species for flavoring many food products and for formulation of perfume and medicated balm. It is also used to treat indigestion, stomach ulcers, liver disorders, and, as emmenagogue, diaphoretic, diuretic, nervine, and aphrodisiac. We examined antioxidant properties and bioactive compounds in various solvent extracts from the seeds of M. fragrans. Methanol, ethanol, and acetone extracts exhibited relatively strong antioxidant activities by 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), superoxide radical, and hydroxyl radical scavenging tests. Furthermore, methanol extracts also displayed significant anti-α-glucosidase activity. Examined and compared to the various solvent extracts for their chemical compositions using HPLC analysis, we isolated the ten higher content compounds and analyzed antioxidant and anti-α-glucosidase activities. Among the isolates, dehydrodiisoeugenol, malabaricone B and malabaricone C were main antioxidant components in seeds of M. fragrans. Malabaricone C exhibited stronger antioxidant capacities than others based on lower half inhibitory concentration (IC50) values in DPPH and ABTS radical scavenging assays, and it also showed significant inhibition of α-glucosidase. These results shown that methanol was found to be the most efficient solvent for extracting the active components from the seeds of M. fragrans, and this material is a potential good source of natural antioxidant and α-glucosidase inhibitor.

Measuring Three-Dimensional Strain and Structural Defects in a Single InGaAs Nanowire Using Coherent X-ray Multiangle Bragg Projection Ptychography.

III-As nanowires are candidates for near-infrared light emitters and detectors that can be directly integrated onto silicon. However, nanoscale to microscale variations in structure, composition, and strain within a given nanowire, as well as variations between nanowires, pose challenges to correlating microstructure with device performance. In this work, we utilize coherent nanofocused X-rays to characterize stacking defects and strain in a single InGaAs nanowire supported on Si. By reconstructing diffraction patterns from the 21̅1̅0 Bragg peak, we show that the lattice orientation varies along the length of the wire, while the strain field along the cross-section is largely unaffected, leaving the band structure unperturbed. Diffraction patterns from the 011̅0 Bragg peak are reproducibly reconstructed to create three-dimensional images of stacking defects and associated lattice strains, revealing sharp planar boundaries between different crystal phases of wurtzite (WZ) structure that contribute to charge carrier scattering. Phase retrieval is made possible by developing multiangle Bragg projection ptychography (maBPP) to accommodate coherent nanodiffraction patterns measured at arbitrary overlapping positions at multiple angles about a Bragg peak, eliminating the need for scan registration at different angles. The penetrating nature of X-ray radiation, together with the relaxed constraints of maBPP, will enable the in operando imaging of nanowire devices.

Template-Assisted Scalable Nanowire Networks.

Topological qubits based on Majorana Fermions have the potential to revolutionize the emerging field of quantum computing by making information processing significantly more robust to decoherence. Nanowires are a promising medium for hosting these kinds of qubits, though branched nanowires are needed to perform qubit manipulations. Here we report a gold-free templated growth of III-V nanowires by molecular beam epitaxy using an approach that enables patternable and highly regular branched nanowire arrays on a far greater scale than what has been reported thus far. Our approach relies on the lattice-mismatched growth of InAs on top of defect-free GaAs nanomembranes yielding laterally oriented, low-defect InAs and InGaAs nanowires whose shapes are determined by surface and strain energy minimization. By controlling nanomembrane width and growth time, we demonstrate the formation of compositionally graded nanowires with cross-sections less than 50 nm. Scaling the nanowires below 20 nm leads to the formation of homogeneous InGaAs nanowires, which exhibit phase-coherent, quasi-1D quantum transport as shown by magnetoconductance measurements. These results are an important advance toward scalable topological quantum computing.

LINE-1 transcription activates long-range gene expression.

Long interspersed nuclear element-1 (LINE-1 or L1) is a retrotransposon group that constitutes 17% of the human genome and shows variable expression across cell types. However, the control of L1 expression and its function in gene regulation are incompletely understood. Here we show that L1 transcription activates long-range gene expression. Genome-wide CRISPR-Cas9 screening using a reporter driven by the L1 5' UTR in human cells identifies functionally diverse genes affecting L1 expression. Unexpectedly, altering L1 expression by knockout of regulatory genes impacts distant gene expression. L1s can physically contact their distal target genes, with these interactions becoming stronger upon L1 activation and weaker when L1 is silenced. Remarkably, L1s contact and activate genes essential for zygotic genome activation (ZGA), and L1 knockdown impairs ZGA, leading to developmental arrest in mouse embryos. These results characterize the regulation and function of L1 in long-range gene activation and reveal its importance in mammalian ZGA.

Chemical reactivity of the tryptophan/acetone/DMSO triad system and its potential applications in nanomaterial synthesis.

Previously, we reported a novel browning reaction of amino acids and proteins in an organic solvent mixture composed of dimethyl sulfoxide (DMSO) and acetone. The reaction proceeds under surprisingly mild conditions, requiring no heating or additional reactants or catalysts. This present study aimed to investigate the chemical reactivity of the triad reaction system of l-tryptophan/aectone/DMSO. We demonstrated that, in DMSO, l-tryptophan initially catalyzed the self-aldol condensation of acetone, resulting in the formation of mesityl oxide (MO). Furthermore, we showed that the three-component system evolved into a diverse chemical space, producing various indole derivatives with aldehyde or ketone functional groups that exhibited self-assembling and nanoparticle-forming capabilities. We highlight the potential applications in nanomaterial synthesis.

Improved super-elastic Ti-Ni alloy wire for treating adult skeletal class III with facial asymmetry: A case report.

BACKGROUND: Correcting severe skeletal class III malocclusion with facial asymmetry in adults through orthodontic treatment alone is difficult. CASE SUMMARY: In this case report, we describe orthodontic treatment and lower incisor extraction without orthognathic surgery for a 27-year-old man with a transverse discrepancy. The extraction sites were closed using an elastic chain. The use of intermaxillary elastics, improved super-elastic Ti-Ni alloy wire, and unilateral multibend edgewise arch wire was crucial for correcting facial asymmetry and the midline deviation. CONCLUSION: After treatment, the patient had a more symmetrical facial appearance, acceptable overjet and overbite, and midline coincidence. The treatment results remained stable 3 years after treatment. This case report demonstrates that a minimally invasive treatment can successfully correct severe skeletal class III malocclusion with facial asymmetry.

Hypericum sampsonii exhibits anti-inflammatory activity in a lipopolysaccharide-induced sepsis mouse model.

Background and aim: Sepsis causes an uncontrolled systemic response characterized by excessive inflammation and immune suppression, leading to multiple organ failure and death. An effective therapeutic strategy for sepsis-related syndromes is urgently needed. Hypericum sampsonii Hance (HS) is a folk herbal plant used to treat arthritis and dermatitis, but the anti-inflammatory properties of HS and its related compounds have rarely been investigated. In this study, we aimed to explore the anti-inflammatory effects of HS. Experimental procedure: Models of bacterial lipopolysaccharide (LPS)-induced activated macrophages and endotoxemia mice were used, in which the TLR4/NF-κB signaling pathway is upregulated to trigger inflammatory responses. The HS extract (HSE) was delivered into LPS-induced endotoxemia mice via oral administration. Three compounds were purified using column chromatography and preparative thin layer chromatography and were validated by physical and spectroscopic data. Results: HSE suppressed NF-κB activation and proinflammatory molecules (TNF-α, IL-6, iNOS) in LPS-activated RAW 264.7 macrophages. Furthermore, oral administration of HSE (200 mg/kg) to LPS-treated mice improved the survival rate, restored body temperature, decreased TNF-α and IL-6 in serum, and reduced IL-6 expression in bronchoalveolar lavage fluid (BALF). In lung tissues, HSE reduced LPS-induced leukocyte infiltration and the expression of proinflammatory molecules (TNF-α, IL-6, iNOS, CCL4 and CCL5). Three pure compounds isolated from HSE, including 2,4,6-trihydroxybenzophenone-4-O-geranyl ether, 1-hydroxy-7 methoxyxanthone and euxanthone, were demonstrated to exhibit anti-inflammatory activities in LPS-stimulated RAW 264.7 macrophages. Conclusion: The present study demonstrated the anti-inflammatory effects of HS in vitro and in vivo. Further clinical studies of HS in human sepsis are warranted.

Bioreduction mechanisms of high-concentration hexavalent chromium using sulfur salts by photosynthetic bacteria.

Eliminating "sulfur starvation" caused by competition for sulfate transporters between chromate and sulfate is crucial to enhance the content of sulfur-containing compounds and improve the tolerance and reduction capability of Cr(VI) in bacteria. In this study, the effects of sulfur salts on the Cr(VI) bioremediation and the possible mechanism were investigated in Rhodobacter sphaeroides SC01 by cell imaging, spectroscopy, and biochemical measurements. The results showed that, when the concentration of metabisulfite was 2.0 g L-1, and the initial OD600 was 0.33, the reduction rate of R. sphaeroides SC01 reached up to 91.3% for 500 mg L-1 Cr(VI) exposure at 96 h. Moreover, thiosulfate and sulfite also markedly increased the concentration of reduced Cr(VI) in R. sphaeroides SC01. Furthermore, the characterization results revealed that -OH, -CONH, -COOH, -SO3, -PO3, and -S-S- played a major role in the adsorption of Cr, and Cr(III) reduced by bacteria was bioprecipitated in the production of Cr2P3S9 and CrPS4. In addition, R. sphaeroids SC01 combined with metabisulfite significantly increased the activity of glutathione peroxidase and the content of glutathione (GSH) and total sulfhydryl while decreasing reactive oxygen species (ROS) accumulation and cell death induced by Cr(VI) toxic. Overall, the results of this research revealed a highly efficient and reliable strategy for Cr(VI) removal by photosynthetic bacteria combined with sulfur salts in high-concentration Cr(VI)-contaminated wastewater.

GLP-1 RAs and SGLT-2 Inhibitors for Insulin Resistance in Nonalcoholic Fatty Liver Disease: Systematic Review and Network Meta-Analysis.

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce glycaemia and weight and improve insulin resistance (IR) via different mechanisms. We aim to evaluate and compare the ability of GLP-1 RAs and SGLT-2 inhibitors to ameliorate the IR of nonalcoholic fatty liver disease (NAFLD) patients. Data Synthesis: Three electronic databases (Medline, Embase, PubMed) were searched from inception until March 2021. We selected randomized controlled trials comparing GLP-1 RAs and SGLT-2 inhibitors with control in adult NAFLD patients with or without T2DM. Network meta-analyses were performed using fixed and random effect models, and the mean difference (MD) with corresponding 95% confidence intervals (CI) were determined. The within-study risk of bias was assessed with the Cochrane collaborative risk assessment tool RoB. Results: 25 studies with 1595 patients were included in this network meta-analysis. Among them, there were 448 patients, in 6 studies, who were not comorbid with T2DM. Following a mean treatment duration of 28.86 weeks, compared with the control group, GLP-1 RAs decreased the HOMA-IR (MD [95%CI]; -1.573[-2.523 to -0.495]), visceral fat (-0.637[-0.992 to -0.284]), weight (-2.394[-4.625 to -0.164]), fasting blood sugar (-0.662[-1.377 to -0.021]) and triglyceride (- 0.610[-1.056 to -0.188]). On the basis of existing studies, SGLT-2 inhibitors showed no statistically significant improvement in the above indicators. Compared with SGLT-2 inhibitors, GLP-1 RAs decreased visceral fat (-0.560[-0.961 to -0.131]) and triglyceride (-0.607[-1.095 to -0.117]) significantly. Conclusions: GLP-1 RAs effectively improve IR in NAFLD, whereas SGLT-2 inhibitors show no apparent effect. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/PROSPERO/, CRD42021251704.

3D Bragg Coherent Diffraction Imaging of Extended Nanowires: Defect Formation in Highly Strained InGaAs Quantum Wells.

InGaAs quantum wells embedded in GaAs nanowires can serve as compact near-infrared emitters for direct integration onto Si complementary metal oxide semiconductor technology. While the core-shell geometry in principle allows for a greater tuning of composition and emission, especially farther into the infrared, the practical limits of elastic strain accommodation in quantum wells on multifaceted nanowires have not been established. One barrier to progress is the difficulty of directly comparing the emission characteristics and the precise microstructure of a single nanowire. Here we report an approach to correlating quantum well morphology, strain, defects, and emission to understand the limits of elastic strain accommodation in nanowire quantum wells specific to their geometry. We realize full 3D Bragg coherent diffraction imaging (BCDI) of intact quantum wells on vertically oriented epitaxial nanowires, which enables direct correlation with single-nanowire photoluminescence. By growing In0.2Ga0.8As quantum wells of distinct thicknesses on different facets of the same nanowire, we identified the critical thickness at which defects are nucleated. A correlation with a traditional transmission electron microscopy analysis confirms that BCDI can image the extended structure of defects. Finite element simulations of electron and hole states explain the emission characteristics arising from strained and partially relaxed regions. This approach, imaging the 3D strain and microstructure of intact nanowire core-shell structures with application-relevant dimensions, can aid the development of predictive models that enable the design of new compact infrared emitters.

Prevalence and Related Factors of White Coat Hypertension and Masked Hypertension in Shunde District, Southern China.

Background: White coat hypertension (WCH) and masked hypertension (MH) can increase the risk of target organ damage. Home blood pressure monitoring is an important method for detecting WCH and MH. However, the prevalence and related factors of WCH and MH in China have been rarely reported. Objective: To explore the prevalence and related factors associated with white coat hypertension (WCH) and masked hypertension (MH) in Shunde District, Southern China. Methods: This study recruited subjects from the Physical Examination Center in Shunde Hospital, Southern Medical University. Office blood pressure and home blood pressure values were collected using the home blood pressure monitor with telemedicine device and office blood pressure monitor, and the prevalence of WCH and MH was calculated by the values. Multivariate logistic regression was used to explore the related factors for WCH and MH. Results: Four-hundred and sixty-one participants (61% male), with an average age of 49 years, were included. The prevalence of WCH and MH was 5.1 and 15.2%, respectively. Multivariate logistic regression analysis showed that smoking (OR = 4.71, 95% CI = 1.05-21.15) and family history of coronary heart disease (OR = 4.51, 95% CI = 1.08-18.93) were associated with higher odds of WCH. The associated factors for higher odds of MH were smoking (OR = 2.83, 95% CI = 1.11-7.23), family history of hypertension (OR = 2.17, 95% CI = 1.11-4.26) and family history of coronary heart disease (OR = 2.82, 95% CI = 1.07-7.45). Conclusion: WCH and MH are highly prevalent in the Physical Examination Center in Shunde Hospital, Southern Medical University. We found smoking and family history of coronary heart disease were related factors for WCH, and smoking, family history of hypertension and coronary heart disease were associated with the odds of MH. Home blood pressure monitoring with a telemedicine device should be recommended to identity abnormal BP phenotype.

A prospective cohort study of home blood pressure monitoring based on an intelligent cloud platform (the HBPM-iCloud study): rationale and design.

BACKGROUND: Hypertension, as a predominant risk factor for cardiovascular disease, is a severe public health burden in China. Home blood pressure monitoring (HBPM) is an important tool in the detection and management of hypertension. However, there is a lack of HBPM data from prospective cohorts in China. Hence, we designed this study to investigate the impact of HBPM on major health outcomes in Chinese population participating in regular health check-ups. METHODS: Leveraging telemedicine technology, the open prospective, multicenter, HBPM-iCloud (Home Blood Pressure Monitoring Based on an Intelligent Cloud Platform) cohort study will recruit participants from three participating health check-up centers in southern China to participate in cloud-based HBPM for 1 week. The prevalence of sustained hypertension, white coat hypertension (WCH), masked hypertension (MH), white coat uncontrolled hypertension (WUCH), and masked uncontrolled hypertension (MUCH) will be defined by a combination of average readings of home-based and office-based blood pressure (BP). Cardiovascular risk factors and subclinical target organ damage will be recorded. Participants will be followed-up for 5 years to examine the incidence and associated risk factors of composite major adverse cardiovascular and cerebrovascular event. CONCLUSION: The study will help to determine the best way to implement telemedicine technology in BP control for better prevention and treatment of hypertension. Results will provide data for a Chinese population to aid in the construction of screening, risk stratification, and intervention strategies for abnormal BP phenotypes, including WCH, MH, WUCH, and MUCH.

Imprecise DNMT1 activity coupled with neighbor-guided correction enables robust yet flexible epigenetic inheritance.

The epigenome, including DNA methylation, is stably propagated during mitotic division. However, single-cell clonal expansion produces heterogeneous methylomes, thus raising the question of how the DNA methylome remains stable despite constant epigenetic drift. Here, we report that a clonal population of DNA (cytosine-5)-methyltransferase 1 (DNMT1)-only cells produces a heterogeneous methylome, which is robustly propagated on cell expansion and differentiation. Our data show that DNMT1 has imprecise maintenance activity and possibly possesses weak de novo activity, leading to spontaneous 'epimutations'. However, these epimutations tend to be corrected through a neighbor-guided mechanism, which is likely to be enabled by the environment-sensitive de novo activity ('tuner') and maintenance activity ('stabilizer') of DNMT1. By generating base-resolution maps of de novo and maintenance activities, we find that H3K9me2/3-marked regions show enhanced de novo activity, and CpG islands have both poor maintenance and de novo activities. The imprecise epigenetic machinery coupled with neighbor-guided correction may be a fundamental mechanism underlying robust yet flexible epigenetic inheritance.