Integrated Chemoenzymatic Approach to Streamline the Assembly of Complex Glycopeptides in the Liquid Phase.

Glycosylation of proteins is a complicated post-translational modification. Despite the significant progress in glycoproteomics, accurate functions of glycoproteins are still ambiguous owing to the difficulty in obtaining homogeneous glycopeptides or glycoproteins. Here, we describe a streamlined chemoenzymatic method to prepare complex glycopeptides by integrating hydrophobic tag-supported chemical synthesis and enzymatic glycosylations. The hydrophobic tag is utilized to facilitate peptide chain elongation in the liquid phase and expeditious product separation. After removal of the tag, a series of glycans are installed on the peptides via efficient glycosyltransferase-catalyzed reactions. The general applicability and robustness of this approach are exemplified by efficient preparation of 16 well-defined SARS-CoV-2 O-glycopeptides, 4 complex MUC1 glycopeptides, and a 31-mer glycosylated glucagon-like peptide-1. Our developed approach will open up a new range of easy access to various complex glycopeptides of biological importance.

Diversity-Oriented Chemoenzymatic Synthesis of Sulfated and Nonsulfated Core 2 O-GalNAc Glycans.

A diversity-oriented chemoenzymatic approach for the collective preparation of sulfated core 2 O-GalNAc glycans and their nonsulfated counterparts was described. A sulfated trisaccharide and a nonsulfated trisaccharide were chemically synthesized by combining flexible protected group manipulations and sequential one-pot glycosylations. The divergent enzymatic extension of these two trisaccharides, using a panel of robust glycosyltransferases that can recognize sulfated substrates and differentiating the branches with specifically designed glycosylation sequences to achieve regioselective sialylation, provided 36 structurally well-defined O-GalNAc glycans.

Clutter Suppression Method for Off-Grid Effects Mitigation in Airborne Passive Radars with Contaminated Reference Signals.

For an airborne passive radar with contaminated reference signals, the clutter caused by multipath (MP) signals involved in the reference channel (MP clutter) corrupts the covariance estimation in space-time adaptive processing (STAP). In order to overcome the severe STAP performance degradation caused by impure reference signals and off-grid effects, a novel MP clutter suppression method based on local search is proposed for airborne passive radar. In the proposed method, the global dictionary is constructed based on the sparse measurement model of MP clutter, and the global atoms that are most relevant to the residual are selected. Then, the local dictionary is designed iteratively, and local searches are performed to match real MP clutter points. Finally, the off-grid effects are mitigated, and the MP clutter is suppressed from all matched atoms. A range of simulations is conducted in order to demonstrate the effectiveness of the proposed method.

Evaluation of root resorption after comprehensive orthodontic treatment using cone beam computed tomography (CBCT): a meta-analysis.

BACKGROUND: Orthodontic treatment can result in root resorption (RR). Traditional two-dimensional (2D) data exhibit magnification, deformation and positioning problems. Cone beam computed tomography (CBCT) contains more accurate three-dimensional (3D) information. This study identified and qualified the extent and location of root resorption using cone beam computed tomography (CBCT) after comprehensive orthodontic treatment. METHODS: Studies comparing the RR before and after comprehensive orthodontic treatment using CBCT were identified using electronic searches of databases, including Cochrane, PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) and Web of Science, and manual searches in relevant journals and the reference lists of the included studies until Oct 25, 2017. The extraction of data and the risk of bias evaluation were conducted by two investigators independently. The methodological quality of the included studies was assessed using the methodological index for non-randomized studies (MINORS). Studies that reported the length and volume of teeth were used for quantitative analyses. RESULTS: Twelve studies were included in the meta-analysis. The length of all teeth after intervention was significantly shorter than that before treatment (MD = 0.80, 95% CI 0.56, 1.03, P < 0.00001). The sequence of RR from heaviest to lightest was maxillary lateral incisors, maxillary central incisors, mandibular anterior teeth, and maxillary canines. Studies were divided into two subgroups based on the use of tooth extraction. Root shortening after treatment was observed in both groups, and extraction caused more root resorption than was observed in the non-extraction group. CONCLUSIONS: There were different degrees of root resorption after orthodontics, but it was clinically acceptable. Root resorption established in CBCT research was less serious and more accurate than that observed in the two-dimensional research. Current evidence suggests that root length and volume were reduced after orthodontic treatment. The order of the amount of RR was maxillary lateral incisors, maxillary central incisors and mandibular anterior teeth. Most of the articles were complicated by different confounding factors. Therefore, more high-quality clinical trials are needed to determine the risk factors of root resorption and optimal protocols for treatment and to draw more reliable conclusions.

Olig2-Targeted G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Survival in Response to Lysolecithin-Induced Demyelination.

Demyelinating diseases, such as multiple sclerosis, are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination; however, the underlying molecular mechanisms remain unclear. Here, we performed genome occupancy analysis by chromatin immunoprecipitation sequencing in oligodendrocytes in response to lysolecithin-induced injury and found that Olig2 and its downstream target Gpr17 are critical factors in regulating oligodendrocyte survival. After injury to oligodendrocytes, Olig2 was significantly upregulated and transcriptionally targeted the Gpr17 locus. Gpr17 activation inhibited oligodendrocyte survival by reducing the intracellular cAMP level and inducing expression of the pro-apoptotic gene Xaf1 The protein kinase A signaling pathway and the transcription factor c-Fos mediated the regulatory effects of Gpr17 in oligodendrocytes. We showed that Gpr17 inhibition elevated Epac1 expression and promoted oligodendrocyte differentiation. The loss of Gpr17, either globally or specifically in oligodendrocytes, led to an earlier onset of remyelination after myelin injury in mice. Similarly, pharmacological inhibition of Gpr17 with pranlukast promoted remyelination. Our findings indicate that Gpr17, an Olig2 transcriptional target, is activated after injury to oligodendrocytes and that targeted inhibition of Gpr17 promotes oligodendrocyte remyelination. SIGNIFICANCE STATEMENT: Genome occupancy analysis of oligodendrocytes in response to lysolecithin-mediated demyelination injury revealed that Olig2 and its downstream target Gpr17 are part of regulatory circuitry critical for oligodendrocyte survival. Gpr17 inhibits oligodendrocyte survival through activation of Xaf1 and cell differentiation by reducing Epac1 expression. The loss of Gpr17 in mice led to precocious myelination and an earlier onset of remyelination after demyelination. Pharmacological inhibition of Gpr17 promoted remyelination, highlighting the potential for Gpr17-targeted therapeutic approaches in demyelination diseases.

Disruption of neurogenesis and cortical development in transgenic mice misexpressing Olig2, a gene in the Down syndrome critical region.

The basic helix-loop-helix (bHLH) transcription factor Olig2 is crucial for mammalian central nervous system development. Human ortholog OLIG2 is located in the Down syndrome critical region in trisomy 21. To investigate the effect of Olig2 misexpression on brain development, we generated a developmentally regulated Olig2-overexpressing transgenic line with a Cre/loxP system. The transgenic mice with Olig2 misexpression in cortical neural stem/progenitor cells exhibited microcephaly, cortical dyslamination, hippocampus malformation, and profound motor deficits. Ectopic misexpression of Olig2 impaired cortical progenitor proliferation and caused precocious cell cycle exit. Massive neuronal cell death was detected in the developing cortex of Olig2-misexpressing mice. In addition, Olig2 misexpression led to a significant downregulation of neuronal specification factors including Ngn1, Ngn2 and Pax6, and a defect in cortical neurogenesis. Chromatin-immunoprecipitation and sequencing (ChIP-Seq) analysis indicates that Olig2 directly targets the promoter and/or enhancer regions of Nfatc4, Dscr1/Rcan1 and Dyrk1a, the critical neurogenic genes that contribute to Down syndrome phenotypes, and inhibits their expression. Together, our study suggests that Olig2 misexpression in neural stem cells elicits neurogenesis defects and neuronal cell death, which may contribute to developmental disorders including Down syndrome, where OLIG2 is triplicated on chromosomal 21.

Direct visualization of membrane architecture of myelinating cells in transgenic mice expressing membrane-anchored EGFP.

Myelinogenesis is a complex process that involves substantial and dynamic changes in plasma membrane architecture and myelin interaction with axons. Highly ramified processes of oligodendrocytes in the central nervous system (CNS) make axonal contact and then extrapolate to wrap around axons and form multilayer compact myelin sheathes. Currently, the mechanisms governing myelin sheath assembly and axon selection by myelinating cells are not fully understood. Here, we generated a transgenic mouse line expressing the membrane-anchored green fluorescent protein (mEGFP) in myelinating cells, which allow live imaging of details of myelinogenesis and cellular behaviors in the nervous systems. mEGFP expression is driven by the promoter of 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNP) that is expressed in the myelinating cell lineage. Robust mEGFP signals appear in the membrane processes of oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system (PNS), wherein mEGFP expression defines the inner layers of myelin sheaths and Schmidt-Lanterman incisures in adult sciatic nerves. In addition, mEGFP expression can be used to track the extent of remyelination after demyelinating injury in a toxin-induced demyelination animal model. Taken together, the membrane-anchored mEGFP expression in the new transgenic line would facilitate direct visualization of dynamic myelin membrane formation and assembly during development and process remodeling during remyelination after various demyelinating injuries.

Visible-Light-Promoted α-C(sp3)-H Amination of Ethers with Azoles and Amides.

A visible-light-induced highly efficient C(sp3)-H amination of ethers with amides and azoles has been presented under mild conditions via a nitrogen- and carbon-centered radical coupling process. This protocol successfully utilizes 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and tert-butyl nitrite (TBN) as cocatalysts to deliver the aminated products of ethers under aerobic conditions. Notably, the developed reaction features the corresponding products in good yields (up to 93%) with a wide substrate scope. The mechanistic study indicates that C-N bond formation proceeds via a direct radical cross-coupling process. Preliminary biological activity analysis indicates that the resulting products have good and selective inhibitory activity on osteosarcoma (OS) cell lines and are promising for use as hits for drug discovery.

Knowledge, attitude, and practice of e-cigarette use among undergraduate students: A comparative study between China and Indonesia.

INTRODUCTION: The health risks associated with e-cigarettes are currently the focus of tobacco control efforts and public health initiatives. Given that China and Indonesia have the highest rates of adult smoking worldwide, it is imperative to gain a comprehensive understanding of e-cigarette prevalence among college students in these two nations. METHODS: From May to June 2023, a cross-sectional study was employed to conduct an online questionnaire survey among college students in three universities located in Kunming (China) and Jakarta (Indonesia), respectively. The chi-squared test was utilized to compare the rates/ratios, while binary logistic regression analysis was applied to examine the factors influencing e-cigarette knowledge, attitude, and practice. RESULTS: A total of 1327 individuals were included in the investigation. The proportion of Indonesian students (75.6%) with a high level of e-cigarette knowledge was lower than that observed among Chinese students (87.4%) (χ2=29.7, p<0.001). Additionally, the prevalence of e-cigarette use among Indonesian students (9.4%) was higher compared to their Chinese counterparts (3.0%) (χ2=22.32, p<0.001). Binary logistic regression analysis revealed that age, place of residence, studies, gender, and e-cigarette use by friends and family, significantly influenced knowledge levels and attitudes toward e-cigarettes in both countries (p<0.05). CONCLUSIONS: Despite the positive knowledge, attitudes, and practices towards e-cigarettes among undergraduate students in both countries, a notable knowledge gap exists concerning the harmful effects of e-cigarettes. Chinese students had better e-cigarette knowledge and demonstrated lower usage rates, suggesting that heightened awareness plays a favorable role in preventing e-cigarette use. Furthermore, it becomes imperative for policymakers and health educators to focus on specific factors, such as the influence of close friends and family members, as well as the area of residence.

Proteomics analysis of human umbilical vein endothelial cells treated with resveratrol.

In the past decade, the small polyphenol resveratrol has received widespread attention as either a potential therapy or as a preventive agent for numerous age-related chronic diseases, including cardiovascular atherosclerosis, cancer, hypertension, and diabetes, but the biological processes and molecular pathways by which resveratrol induces these beneficial effects, as well as its safety and toxicology remain largely undefined. To explore the molecular mechanisms of resveratrol involved in the amelioration of endothelial dysfunction and vascular disease, in the present study the protein profile changes of human umbilical vein endothelial cells in response to resveratrol treatment were investigated using proteomics approaches (2-DE combined with MS/MS). As a result, four down-regulated protein species named elongation factor 2 (EEF2), carboxymethyl-cofilin-1 (cofilin-1), acetyl-eukaryotic translation initiation factor 5A-1 (acetyl-EIF5A) and barrier-to-autointegration factor, and five up-regulated protein species named heat shock protein beta-1 (HSP27), phospho-HSP27, phospho-stathmin, Nicotinate-nucleotide pyrophosphorylase and 1,2-dihydroxy-3-keto-5-methylthiopentene dioxygenase were identified. Among them, two translation-related protein species (EEF2 and acetyl-EIF5A) were the most significantly changed (over tenfold). Phospho-EEF2 was further verified to be dramatically up-regulated by immunoblot assays. It is notable that in the present study several protein species with post-transcriptional modification (carboxymethyl-, acetyl-, and phospho-) were found to be altered following exposure to resveratrol. These findings may improve our understanding of the molecular mechanisms underlying the pleiotropic effects of resveratrol on endothelial cells.

Effect of Process Parameters on the Performance of Drop-On-Demand 3D Inkjet Printing: Geometrical-Based Modeling and Experimental Validation.

As additive manufacturing has evolved, 3D inkjet printing (IJP) has become a promising alternative manufacturing method able to manufacture functional multi-material parts in a single process. However, issues with part quality in terms of dimensional errors and lack of precision still restrict its industrial and commercial applications. This study aims at improving the dimensional accuracy of 3D IJP parts by developing an optimization-oriented simulation tool of droplet behavior during the drop-on-demand 3D IJP process. The simulation approach takes into consideration the effect of droplet volume, droplet center-to-center distance, coverage percentage of jetted droplets, the contact angle of the ink on the solid substrate and coalescence performance of overlapping droplets, in addition to the number of printed layers. Following the development of the simulation tool using MATLAB, its feasibility was experimentally validated and the results showed a good agreement with a maximum deviation of 2.25% for horizontal features. In addition, the simulated horizontal features are compared with the results of "Inkraster" software, which also illustrates droplet behavior, however, only in 2D. For vertical features, a dial gauge indicator is used to measure the sample height, and the validation results show that the simulation tool can predicate the height of the sample with an average error of 10.89% for a large droplet diameter and 8.09% for a small diameter. The simulation results were found to be in a good agreement with the dimensions of the printed parts. The developed tool was then used to elucidate the effect of resolution of processed TIFF image and droplet diameter on the dimensional accuracy of 3D IJP parts.

Enantioselective Construction of C3-Multifunctionalization α-Hydroxy-ß-amino Pyridines via α-Pyridyl Diazoacetate, Water, and Imines for Drug Hunting.

An asymmetric catalytic approach for the construction of C3-multifunctionalization α-hydroxy-ß-amino pyridines has been reported. The products can be accessed by the modulation of two chiral catalysts independently in high yield and with good enantioselectivity. The method features mild reaction conditions and an excellent functional group tolerance. Biological activity analysis shows that the resulting products have a selective antiosteosarcoma activity on 143B cells.

LIN28B inhibition sensitizes cells to p53-restoring PPI therapy through unleashed translational suppression.

p53 is the most highly mutated tumor suppressor across multiple types of human cancers. The level and function of p53 are fine-tuned through multifaced mechanisms in which the protein-protein interaction between p53 and MDM2 is considered as a major circuit. Recent studies suggest therapeutic strategy attempts to restore p53 function by small molecule inhibitors targeting p53-MDM2 interaction can be a promising direction in treating cancers with wild-type or functional p53. Currently, clinical tests of the p53-MDM2 protein-protein interaction inhibitors (PPIs) are underway. However, it remains elusive about the biomarkers that may predict the therapeutic responses to those inhibitors. Here we report that RNA-binding protein LIN28B directly regulates p53 through binding to the 5'΄ untranslated region of p53 mRNA and blocks its translation by competing with a translation enhancer protein, ribosomal protein L26 (RPL26). This regulatory mechanism of LIN28B does not involve let-7 maturation or the canonical protein turnover pathway of p53. Furthermore, we show that inhibition of LIN28B unleashes the translational suppression of p53 through RPL26, and leads to enhanced sensitivities of cancer cells to inhibitors of p53-MDM2 interaction. Together, we demonstrate a competitive regulatory mechanism of p53 by LIN28B, which has important implications in developing biomarkers to the therapies aiming to reinstate p53 function.

Novel 2-phenyl-3-(Pyridin-2-yl) thiazolidin-4-one derivatives as potent inhibitors for proliferation of osteosarcoma cells in vitro and in vivo.

Due to unknown pathogenesis and unidentified drug target, no drug for the treatment of osteosarcoma (OS) has been launched to the market. Herein, thiazolidinone 1a was discovered as a hit compound by phenotypic screening with an in-house patrimonial collection of structural diversity. The following SAR (Structure-Activity Relationship) study affords the final water-soluble lead compound (R)-8i as a potential inhibitor for the proliferation of OS cells by the modulation of solubility of the compounds with remarkable cellular potency (IC50 = 21.9 nM for MNNG/HOS cells) and in vivo efficacy (52.9% inhibition OS growth in mice), as well as pharmacokinetic properties. (R)-8i also significantly suppresses OS cell migration in vitro and showed to be well-tolerated. Our preliminary investigation shows that the effects of (R)-8i are not dependent on p53 and myoferlin (MYOF). These results suggest that (R)-8i might be a potential drug candidate for OS treatment.

Detection of Long Noncoding RNA Expression by Real-Time PCR.

Recent advances in sequencing technology and bioinformatic analysis promote the identification of long noncoding RNA (lncRNA), a novel form of untranslated RNA transcript. Long coding RNA has been extensively investigated for its fundamental biological functions in a broad spectrum of pathogenetic and therapeutic studies. The level of lncRNA expression varies among different tissue types and contexts. Therefore, a quantitative method to accurately measure lncRNA expression is highly desired. Real-time PCR analysis enables us to conveniently determine the identity and abundance of lncRNA in a time-efficient manner. Here, we introduce how to use real-time PCR to analyze and quantify a defined lncRNA.

Emerging role of SWI/SNF complex deficiency as a target of immune checkpoint blockade in human cancers.

Mammalian SWI/SNF complex is a key chromatin remodeler that reshapes nucleosomes and regulates DNA accessibility. Mutations in SWI/SNF subunits are found in a broad spectrum of human cancers; however, the mechanisms of how these aberrations of SWI/SNF complex would impact tumorigenesis and cancer therapeutics remain to be elucidated. Studies have demonstrated that immune checkpoint blockade (ICB) therapy is promising in cancer treatment. Nevertheless, suitable biomarkers that reliably predict the clinical response to ICB are still lacking. Emerging evidence has suggested that SWI/SNF components play novel roles in the regulation of anti-tumor immunity, and SWI/SNF deficiency can be therapeutically targeted by ICB. These findings manifest the prominence of the SWI/SNF complex as a stratification biomarker that predicts treatment (therapeutic) response to ICB. In this review, we summarize the recent advances in ICB therapy by harnessing the cancer-specific vulnerability elicited by SWI/SNF deficiency. We provide novel insights into a comprehensive understanding of the underlying mechanisms by which SWI/SNF functions as a modulator of anti-tumor immunity.

OLIG2 maintenance is not essential for diffuse intrinsic pontine glioma cell line growth but regulates tumor phenotypes.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a pediatric lethal high-grade brainstem glioma with no effective therapies. OLIG2 (oligodendrocyte transcription factor 2) was reported to be critical for the growth of a DIPG cell line CCHMC-DIPG-1. Surprisingly, we found that the CCHMC-DIPG-1 cells express little OLIG2 and exhibit a mesenchymal phenotype, which raised a question regarding the role of OLIG2 in the growth of DIPG cells. METHODS: We evaluated the function of OLIG2 in different DIPG cell lines through molecular and genetic approaches and performed transcriptomic and genomic landscape profiling including whole-genome bisulfite sequencing, RNA-seq, ATAC-seq, and ChIP-seq. shRNA-mediated knockdown and CRISPR-Cas9-mediated knockout approaches were utilized to assess OLIG2 functions in DIPG cell growth. RESULTS: We found that DIPG cells are phenotypically heterogeneous and exhibit the characteristics of distinct malignant gliomas including proneural, classical, and mesenchymal subtypes. OLIG2 knockdown did not impact the growth of CCHMC-DIPG-1 cells, wherein OLIG2 is epigenetically silenced. Moreover, OLIG2 deletion did not substantially impair OLIG2-expressing proneural-like DIPG growth but led to an upregulation of HIPPO-YAP1 and epidermal growth factor receptor (EGFR) signaling and a tumor phenotype shift. Targeting HIPPO-YAP1 and EGFR signaling in OLIG2-deficient DIPG cells inhibited tumor cell growth. CONCLUSIONS: Our data indicate that OLIG2 is dispensable for DIPG growth but regulates the phenotypic switch of DIPG tumor cells. OLIG2 downregulation leads to deregulation of adaptive YAP1 and EGFR signaling. Targeting YAP1 and EGFR pathways inhibits the growth of OLIG2-deficient DIPG cells, pointing to a therapeutic potential by targeting adaptive signaling to treat DIPG tumors with nominal OLIG2 expression.

Microstructure and Mechanical Properties of AlSi7Mg0.6 Aluminum Alloy Fabricated by Wire and Arc Additive Manufacturing Based on Cold Metal Transfer (WAAM-CMT).

Wire and arc additive manufacturing based on cold metal transfer (WAAM-CMT) has aroused wide public concern in recent years as one of the most advanced technologies for manufacturing components with complex geometries. However, the microstructure and mechanical properties of the parts fabricated by WAAM-CMT technology mostly are intolerable for engineering application and should be improved necessarily. In this study, heat treatment was proposed to optimize the microstructure and enhance mechanical properties in the case of AlSi7Mg0.6 alloy. After heat treatment, the division between coarse grain zone and fine grain zone of as-deposited samples seemed to disappear and the distribution of Si and Mg elements was more uniform. What is more, the yield strength and ultimate tensile strength were improved significantly, while the ductility could be sustained after heat treatment. The improvement of strength is attributed to precipitation strengthening, and the shape change of Si phase. No reduction in ductility is due to the higher work hardening rate caused by nanostructured precipitate. It is proved that heat treatment as an effective method can control the microstructure and enhance comprehensive mechanical properties, which will boost rapid development of WAAM industrial technology.

Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis.

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.

Dual Requirement of CHD8 for Chromatin Landscape Establishment and Histone Methyltransferase Recruitment to Promote CNS Myelination and Repair.

Disruptive mutations in chromatin remodeler CHD8 cause autism spectrum disorders, exhibiting widespread white matter abnormalities; however, the underlying mechanisms remain elusive. We show that cell-type specific Chd8 deletion in oligodendrocyte progenitors, but not in neurons, results in myelination defects, revealing a cell-intrinsic dependence on CHD8 for oligodendrocyte lineage development, myelination and post-injury remyelination. CHD8 activates expression of BRG1-associated SWI/SNF complexes that in turn activate CHD7, thus initiating a successive chromatin remodeling cascade that orchestrates oligodendrocyte lineage progression. Genomic occupancy analyses reveal that CHD8 establishes an accessible chromatin landscape, and recruits MLL/KMT2 histone methyltransferase complexes distinctively around proximal promoters to promote oligodendrocyte differentiation. Inhibition of histone demethylase activity partially rescues myelination defects of CHD8-deficient mutants. Our data indicate that CHD8 exhibits a dual function through inducing a cascade of chromatin reprogramming and recruiting H3K4 histone methyltransferases to establish oligodendrocyte identity, suggesting potential strategies of therapeutic intervention for CHD8-associated white matter defects.