Gastric cancer (GC) is a common cause of cancer-related death. The etiology and pathogenesis of GC remain unclear, with genetic and epigenetic factors playing an important role. Previous studies investigated the association of GC with many genetic variants in and promoter hypermethylation of E-cadherin gene (CDH1), with conflicting results reported.To clarify this inconsistency, we conducted updated meta-analyses to assess the association of genetic variants in and the promoter hypermethylation of CDH1 with GC, including C-160A (rs16260) and other less-studied genetic variants,Data sources were PubMed, Cochrane Library, Google Scholar, Web of Knowledge, and HuGE, a navigator for human genome epidemiology.Study eligibility criteria and participant details are as follows: studies were conducted on human subjects; outcomes of interest include GC; report of genotype data of individual genetic variants in (or methylation status of) CDH1 in participants with and without GC (or providing odds ratios [OR] and their variances).Study appraisal and synthesis methods included the use of OR as a measure of the association, calculated from random effects models in meta-analyses. We used I for the assessment of between-study heterogeneity, and publication bias was assessed using funnel plot and Egger test.A total of 33 studies from 30 published articles met the eligibility criteria and were included in our analyses. We found no association between C-160A and GC (OR = 0.88; 95% confidence interval [CI], 0.71-1.08; P = 0.215), assuming an additive model (reference allele C). C-160A was associated with cardia (OR = 0.21; 95% CI, 0.11-0.41; P = 2.60 × 10), intestinal (OR = 0.66; 95% CI, 0.49-0.90; P = 0.008), and diffuse GC (OR = 0.57; 95% CI, 0.40-0.82; P = 0.002). The association of C-160A with noncardia GC is of bottom line significance (OR = 0.65; 95% CI, 0.42-1.01; P = 0.054). Multiple other less-studied genetic variants in CDH1 also exhibited association with GC. Gene-based analysis indicated a significant cumulative association of genetic variants in CDH1 with GC (all Ps <10). Sensitivity analysis excluding studies not meeting Hardy-Weinberg equilibrium (HWE) yielded similar results. Analysis by ethnic groups revealed significant association of C-160A with cardia GC in both Asian and whites, significant association with noncardia GC only in Asians, and no significant association with intestinal GC in both ethnic groups. There was significant association of C160-A with diffuse GC in Asians (P = 0.011) but not in whites (P = 0.081). However, after excluding studies that violate HWE, this observed association is no longer significant (P = 0.126). We observed strong association of promoter hypermethylation of CDH1 with GC (OR = 12.23; 95% CI, 8.80-17.00; P = 1.42 × 10), suggesting that epigenetic regulation of CDH1 could play a critical role in the etiology of GC.Limitations of this study are as follows: we could not adjust for confounding factors; some meta-analyses were based on a small number of studies; sensitivity analysis was limited due to unavailability of data; we could not test publication bias for some meta-analyses due to small number of included studies.We found no significant association of the widely studied genetic variant C-160A, but identified some other genetic variants showing significant association with GC. Future studies with large sample sizes that control for confounding risk factors and/or intensively interrogate CpG sites in CDH1 are needed to validate the results found in this study and to explore additional epigenetic loci that affect GC risk.

Early colonization of gut microbiota in human gut is a complex process. It remains unclear when gut microbiota colonization occurs and how it proceeds. In order to study gut microbiota composition in human early life, the present study recruited 10 healthy pairs of twins, including five monozygotic (MZ) and five dizygotic (DZ) twin pairs, whose age ranged from 0 to 6 years old. 20 fecal samples from these twins were processed by shotgun metagenomic sequencing, and their averaged data outputs were generated as 2G per sample. We used MEGAN5 to perform taxonomic and functional annotation of the metagenomic data, and systematically analyzed those 20 samples, including Jaccard index similarity, principle component, clustering, and correlation analyses. Our findings indicated that within our study group: 1) MZ-twins share more microbes than DZ twins or non-twin pairs, 2) gut microbiota distribution is relatively stable at metabolic pathways level, 3) age represents the strongest factor that can account for variation in gut microbiota, and 4) a clear metabolic pathway shift can be observed, which speculatively occurs around the age of 1 year old. This research will serve as a base for future studies of gut microbiota-related disease research.

The mechanisms that coordinate and balance a complex network of opposing regulators to control Schwann cell (SC) differentiation remain elusive. Here we demonstrate that zinc-finger E-box-binding homeobox 2 (Zeb2, also called Sip1) transcription factor is a critical intrinsic timer that controls the onset of SC differentiation by recruiting histone deacetylases HDAC 1 and 2 (HDAC1/2) and nucleosome remodeling and deacetylase complex (NuRD) co-repressor complexes in mice. Zeb2 deletion arrests SCs at an undifferentiated state during peripheral nerve development and inhibits remyelination after injury. Zeb2 antagonizes inhibitory effectors including Notch and Sox2. Importantly, genome-wide transcriptome analysis reveals a Zeb2 target gene encoding the Notch effector Hey2 as a potent inhibitor for Schwann cell differentiation. Strikingly, a genetic Zeb2 variant associated with Mowat-Wilson syndrome disrupts the interaction with HDAC1/2-NuRD and abolishes Zeb2 activity for SC differentiation. Therefore, Zeb2 controls SC maturation by recruiting HDAC1/2-NuRD complexes and inhibiting a Notch-Hey2 signaling axis, pointing to the critical role of HDAC1/2-NuRD activity in peripheral neuropathies caused by ZEB2 mutations.

Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk-associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53 Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17 However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease.

Epileptic encephalopathies are severe seizure disorders accompanied by intellectual disability. Whole-exome sequencing technology has enabled the discovery of genetic mutations responsible for a wide range of diseases, and severe epilepsy and neurodevelopmental diseases are often associated with rare de novo mutations. We identified a novel de novo frameshift mutation in the PPP3CA gene encoding calcium-dependent protein phosphatase (calcineurin) catalytic subunit A (c.1255_1256del, p.Ser419Cysfs*31) in an 11.5-mo-old female with early-onset refractory epilepsy and developmental delay. This finding expands the list of PPP3CA mutations associated with early-onset severe neurodevelopmental disease with seizures and provides further details on clinical features.

Human breast milk epithelial cells (BMECs) can be isolated and cultured with high purity. Induced pluripotent stem cells (iPSCs) were generated from BMECs with Yamanaka factors (OCT4, SOX2, c-MYC, KLF4) using episomal system. Pluripotency of breast milk-derived iPSCs (BM-iPSCs) was confirmed by the expression of pluripotent markers with immunocytochemistry and spontaneous differentiation of three germ layers in vitro and teratoma formation assay in vivo. Besides, the iPSC lines displayed normal karyotype. Breast milk is a non-invasive and easily accessible cell source, we can obtain BM-iPSCs from BMECs with low costs in a transgene-free episomal system.

Oligodendrocyte precursor cells (OPCs), also known as NG2 glia, arise from neural progenitor cells in the embryonic ganglionic eminences that also generate inhibitory neurons. They are ubiquitously distributed in the central nervous system, remain proliferative through life, and generate oligodendrocytes in both gray and white matter. OPCs exhibit some lineage plasticity, and attempts have been made to reprogram them into neurons, with varying degrees of success. However, little is known about how epigenetic mechanisms affect the ability of OPCs to undergo fate switch and whether OPCs have a unique chromatin environment around neuronal genes that might contribute to their lineage plasticity. Our bioinformatic analysis of histone posttranslational modifications at interneuron genes in OPCs revealed that OPCs had significantly fewer bivalent and repressive histone marks at interneuron genes compared to astrocytes or fibroblasts. Conversely, OPCs had a greater degree of deposition of active histone modifications at bivalently marked interneuron genes than other cell types, and this was correlated with higher expression levels of these genes in OPCs. Furthermore, a significantly higher proportion of interneuron genes in OPCs than in other cell types lacked the histone posttranslational modifications examined. These genes had a moderately high level of expression, suggesting that the "no mark" interneuron genes could be in a transcriptionally "poised" or "transitional" state. Thus, our findings suggest that OPCs have a unique histone code at their interneuron genes that may obviate the need for erasure of repressive marks during their fate switch to inhibitory neurons.

CHARGE syndrome is characterized by coloboma, heart defects, choanal atresia, growth retardation, genitourinary malformation and ear abnormalities. The chromodomain helicase DNA-binding protein 7 (CHD7) gene is the major cause of CHARGE syndrome and is inherited in an autosomal dominant manner. Currently, the phenotype spectrum of CHARGE syndrome in neonatal population remain elusive. We aimed to investigate the phenotype spectrum of neonatal patients suspected to have CHARGE syndrome with pathogenic or likely pathogenic variants in the CHD7 gene.

Mutations in the polycomb repressive complex 2 (PRC2) can cause Weaver-like syndrome, wherein a patient cohort exhibits abnormal white matter; however, PRC2 functions in CNS myelination and regeneration remain elusive. We show here that H3K27me3, the PRC2 catalytic product, increases during oligodendrocyte maturation. Depletion of embryonic ectoderm development (EED), a core PRC2 subunit, reduces differentiation of oligodendrocyte progenitors (OPCs), and causes an OPC-to-astrocyte fate switch in a region-specific manner. Although dispensable for myelin maintenance, EED is critical for oligodendrocyte remyelination. Genomic occupancy and transcriptomic analyses indicate that EED establishes a chromatin landscape that selectively represses inhibitory WNT and bone morphogenetic protein (BMP) signaling, and senescence-associated programs. Blocking WNT or BMP pathways partially restores differentiation defects in EED-deficient OPCs. Thus, our findings reveal that EED/PRC2 is a crucial epigenetic programmer of CNS myelination and repair, while demonstrating a spatiotemporal-specific role of PRC2-mediated chromatin silencing in shaping oligodendrocyte identity and lineage plasticity.

Schwann cell (SC) myelination in the peripheral nervous system is essential for motor function, and uncontrolled SC proliferation occurs in cancer. Here, we show that a dual role for Hippo effectors TAZ and YAP in SC proliferation and myelination through modulating G-protein expression and interacting with SOX10, respectively. Developmentally regulated mutagenesis indicates that TAZ/YAP are critical for SC proliferation and differentiation in a stage-dependent manner. Genome-wide occupancy mapping and transcriptome profiling reveal that nuclear TAZ/YAP promote SC proliferation by activating cell cycle regulators, while targeting critical differentiation regulators in cooperation with SOX10 for myelination. We further identify that TAZ targets and represses Gnas, encoding Gαs-protein, which opposes TAZ/YAP activities to decelerate proliferation. Gnas deletion expands SC precursor pools and blocks peripheral myelination. Thus, the Hippo/TAZ/YAP and Gαs-protein feedback circuit functions as a fulcrum balancing SC proliferation and differentiation, providing insights into molecular programming of SC lineage progression and homeostasis.

The mutation in postoperative plasma (molecular residues) was an independently prognostic factor in colorectal cancer (CRC). The status of postoperative plasma mutation of microsatellite instability (MSI) CRC has not been systematically examined. In this study, we enrolled 30 MSI and 46 microsatellite stability (MSS) CRCs, and performed next generation sequencing on surgical tissues, postoperative plasma, and plasma during follow-up. Compared with MSS, MSI tumors had dissimilar genomic profiles, higher tumor mutation burden (TMB), and more frameshift mutations. In the postoperative plasma, more MSI CRCs were detected with tumor-derived mutations (77% in MSI vs 33% in MSS, p < 0.001). The numbers of postoperative mutations were proportional to MSI tissues (Spearman r = 0.47, p = 0.023), while not for MSS. More proportion of postoperative plasma samples of MSI CRCs harbored frameshift mutations than MSS (p = 0.007). For the follow-up plasma, 93% (14 out of 15) MSI CRCs harbored tumor-derived mutations; 33% (4/12) MSS were mutation-positive, lower than MSI (p = 0.003). Thus, considering that MSI CRC had extremely distinct mutational characteristics in tumor and postoperative plasma compared with MSS CRC, we propose that the prognostic value of molecular residue identification in postoperative plasma needs to be independently evaluated in MSI and MSS CRCs.

Carbohydrate antigen 19-9 (CA19-9) is one of the most widely used tumor markers in gastrointestinal cancer. However, serum CA19-9 is not a recommended routine measurement in colon cancer. In this study, we evaluated the value of the preoperative serum CA19-9 level for the prediction of postoperative prognosis in stage III colon cancer. The medical records of 367 consecutive patients with stage III colon cancer who underwent curative resection followed by adjuvant chemotherapy with oxaliplatin and capecitabine between December 2007 and April 2015 were retrospectively reviewed. We determined the optimal cutoff value of CA19-9 for 3-year recurrence using the receiver operating characteristic (ROC) method. Differences in disease-free survival (DFS) and overall survival (OS) rates stratified by CA19-9 level were compared by using Kaplan-Meier and log-rank tests. A Cox proportional hazards model was used to identify prognostic variables for DFS and OS. The statistically determined best cutoff value for CA19-9 was 24 U/ml. High CA19-9 levels (> 24 U/ml) were significantly associated with poorly differentiated tumors, abnormal carcinoembryonic antigen (CEA) levels, and a high cumulative incidence of lung metastasis. Additionally, compared with low CA19-9 levels, high preoperative CA19-9 levels were associated with inferior 3-year DFS and OS rates, especially for high-risk patients (T4Nany or TanyN2). Multivariate analyses revealed that CA19-9 was an independent factor associated with both DFS (hazard ratio [HR], 2.248; 95% confidence interval [CI], 1.393-3.628; P = 0.001) and OS (HR: 2.081; 95% CI: 1.137-3.808; P = 0.017). The results of this study showed that high levels of preoperative serum CA19-9 indicated a worse prognostic outcome for stage III colon cancer patients. An early follow-up protocol to assess lung metastasis and a full course of adjuvant chemotherapy should be used for these patients.

Persistent pulmonary hypertension of the newborn (PPHN) is characterized by sustained high levels of pulmonary vascular resistance after birth with etiology unclear; Arterial blood oxygen saturation of Tibetan newborns at high latitudes is higher than that of Han newborns at low latitudes, suggesting that genetic adaptation may allow sufficient oxygen to confer Tibetan populations with resistance to pulmonary hypertension; We have previously identified genetic factors related to PPHN through candidate gene sequencing; In this study, we first performed whole exome sequencing in PPHN patients to screen for genetic-related factors.

The identity and degree of heterogeneity of glial progenitors and their contributions to brain tumor malignancy remain elusive. By applying lineage-targeted single-cell transcriptomics, we uncover an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Our analysis identifies distinct transitional intermediate states and their divergent developmental trajectories in astroglial and oligodendroglial lineages. Moreover, intersectional analysis uncovers analogous intermediate progenitors during brain tumorigenesis, wherein oligodendrocyte-progenitor intermediates are abundant, hyper-proliferative, and progressively reprogrammed toward a stem-like state susceptible to further malignant transformation. Similar actively cycling intermediate progenitors are prominent components in human gliomas with distinct driver mutations. We further unveil lineage-driving networks underlying glial fate specification and identify Zfp36l1 as necessary for oligodendrocyte-astrocyte lineage transition and glioma growth. Together, our results resolve the dynamic repertoire of common and divergent glial progenitors during development and tumorigenesis and highlight Zfp36l1 as a molecular nexus for balancing glial cell-fate decision and controlling gliomagenesis.

Previous genome-wide association studies (GWAS) have identified potential genetic variants associated with the risk of major depressive disorder (MDD), but the underlying biological interpretation remains largely unknown. We aimed to prioritize genes that were pleiotropically or potentially causally associated with MDD. We applied the summary data-based Mendelian randomization (SMR) method integrating GWAS and gene expression quantitative trait loci (eQTL) data in 13 brain regions to identify genes that were pleiotropically associated with MDD. In addition, we repeated the analysis by using the meta-analyzed version of the eQTL summary data in the brain (brain-eMeta). We identified multiple significant genes across different brain regions that may be involved in the pathogenesis of MDD. The prime-specific gene BTN3A2 (corresponding probe: ENSG00000186470.9) was the top hit showing pleiotropic association with MDD in 9 of the 13 brain regions and in brain-eMeta, after correction for multiple testing. Many of the identified genes are located in the human major histocompatibility complex (MHC) region on chromosome 6 and are mainly involved in the immune response. Our SMR analysis indicated that multiple genes showed pleiotropic association with MDD across the brain regions. These findings provided important leads to a better understanding of the mechanism of MDD and revealed potential therapeutic targets for the prevention and effective treatment of MDD.

Enzyme-based host depletion significantly improves the sensitivity of clinical metagenomics. Recent studies found that real-time adaptive sequencing of DNA molecules was achieved using a nanopore sequencing machine, which enabled effective enrichment of microbial sequences. However, few studies have compared the enzyme-based host depletion and nanopore adaptive sequencing for microbial enrichment efficiency.

A low-phenylalanine (Phe) diet affects the metabolism and diversity of gut microbial communities in children with phenylketonuria (PKU). Our study examined gut microbiota characteristics and metabolic pathways, and their correlations with clinical phenotypes in a high-incidence population.

Poor osseointegration and infection are the main reasons leading to the failure of hard tissue implants; especially, in recent years, the failure rate has been increasing every year owing to the continuously increasing conditions such as injury, trauma, diseases, or infections. Therefore, the development of a biomimetic surface coating of bone tissues with antibacterial function is an effective means to improve bone healing and inhibit bacterial infection. Mimicking the natural bone, in this study, we have designed a silk fibroin (collagen-like structure)-based coating inlaid with nanohydroxyapatite (nHA) and silver nanoparticles (AgNPs) for promoting antibacterial ability and osteogenesis, especially focusing on the bone mimetic structure for enhancing bone health. Observing the morphology and size of the composite nanoparticles by transmission electron microscope (TEM), nHA provided nucleation sites for the formation of AgNPs, forming an nHA/AgNP complex with a size of about 100-200 nm. Characterization of the nHA/Ag-loaded silk fibroin biomimetic coating showed an increased surface roughness with good density and compact performances. The silk fibroin-based coating loaded with uniformly distributed AgNPs and nHA could effectively inhibit the adhesion of Staphylococcus aureus on the surface and, at the same time, quickly kill planktonic bacteria, indicating their good antibacterial ability. In vitro cell experiments revealed that the biomimetic silk fibroin-based coating was beneficial to the adhesion, spreading, and proliferation of osteoblasts (MC3T3-E1). In addition, by characterizing LDH and ROS, it was found that the nHA/Ag complex could significantly reduce the cytotoxicity of AgNPs, and the osteoblasts on the coating surface maintained the structure intact.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD.

Esophageal atresia is a common and life-threatening birth defect with a poorly understood etiology. In this study, we analyzed the sequence variants of coding regions for a set of esophageal atresia-related genes including MYCN, SOX2, CHD7, GLI3, FGFR2 and PTEN for mutations using PCR-based target enrichment and next-generation sequencing in 27 patients with esophageal atresia. Genomic copy number variation analysis was performed using Affymetrix SNP 6.0. We found a de novo heterozygous mutation in the N-terminal region of the GLI3 gene (c.332T>C, p.M111T) in a patient with esophageal atresia and hemivertebrae. The N-terminal region (amino acids 1-397) of GLI3 contains the repressor domain, which interacts with SKI family proteins. Using the co-immunoprecipitation assay, we found that interaction of GLI3 with the SKI family protein SKIL was significantly compromised by the p.M111T mutation of GLI3. Thus far, all the identified mutations mapped within the repressor domain of GLI3 were nonsense and frame-shift mutations. In this study, a missense mutation was initially detected in this region. Our finding is the first to link this GLI3 gene mutation with esophageal atresia in humans, which was previously suggested in an animal model.