📋 Browse Articles

Autism Spectrum Disorder (ASD) involves a multi-system interaction mechanism among genetics, immunity, and gut microbiota, yet its regulatory network remains undefined. This study conducted a meta-analysis on Genome-Wide Association Study data from four independent ASD cohorts to identify potential genetic loci. By integrating Polygenic Priority Score, brain region, and brain cell eQTL enrichment analyses, and combining summary-data-based Mendelian Randomisation (SMR) analyses of brain cis-eQTL and mQTL, bidirectional Mendelian Randomisation analyses of 473 gut microbiota, and SMR analysis of blood eQTL, SNPs such as rs2735307 and rs989134 with significant multi-dimensional associations were identified. These loci exert cross-tissue regulatory effects by participating in gut microbiota regulation, involving immune pathways such as T cell receptor signal activation and neutrophil extracellular trap formation, as well as cis-regulating neurodevelopmental genes (HMGN1 and H3C9P), or synergistically influencing epigenetic methylation modifications to regulate the expression of BRWD1 and ABT1. The cross-scale evidence chain constructed in this study provides a theoretical foundation for precision medicine research in ASD, holding promise to advance the development of innovative therapeutic strategies. Show less

The Sahiwal are among the most prominent international transboundary dairy cattle distributed in large numbers between India and Pakistan. With the elapse of more than seven decades after the independence and limited cross-border exchange of Sahiwal germplasm, one thought-provoking question arises as to whether natural and artificial selection could alter the genomic signature patterns in the Sahiwal, reared for different purposes in these two countries. Deciphering the genetic mechanisms that underlie economic traits is essential for advancement and long-term breeding plans that are reflected in the distinct selection signatures they carry. To identify these genomic signatures, three medium-density SNP datasets of Sahiwal from three geographical locations of India and Pakistan were analyzed, using De-Correlated Composite of Multiple Selection Signals technique to identify the major candidate genes. In the genome of Sahiwal, a total of 70 genomic regions with 261 protein-coding genes were found. Milk production (NEK11, HMGCS1, BTN1A1,KCNH3), reproduction (SH3BGR, PSMG1, BRWD1,B3GALT5) and immune response genes (BPIFB1, MCOLN2) were more closely related to the Indian Sahiwal. Pakistani Sahiwal had genes closely linked with the dual-purpose meat (RALGAPA2, RIN2, CFAP61), and milk (SLC24A3 GALNT17, BACH2) traits. Our findings revealed differential patterns of selection signatures in transboundary Sahiwal cattle. Show less

While previous genome-wide association studies (GWAS) identified multiple risk loci for suicide ideation (SI) and suicide attempt (SA), there is still a limited understanding of the genetic predisposition underlying suicidal behaviors in diverse populations. This study aimed to conduct a large-scale investigation of the suicidality spectrum (SP) to generate new insights into its biology and epidemiology. Leveraging ancestrally diverse participants (SI N This study provides convergent genetic evidence for both shared and phenotype-specific components of suicidal behaviors and delineates their associated factors spanning from proximal clinical and behavioral traits to more distal social determinants. These findings refine our understanding of the etiology of suicidal behaviors and may inform targeted strategies for suicide prevention in both clinical and public health settings. Show less

The increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing to vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct OUD behaviors while maintaining a uniform environment, an experimental design not easily achieved in humans. Furthermore, we used a novel non-linear network-based clustering approach to characterize rats based on OUD vulnerability to assess genetic variants associated with OUD susceptibility. Our findings confirm the heritability of several OUD-like behaviors, including OUD susceptibility. Additionally, several genetic variants associated with nociceptive threshold prior to heroin experience, heroin consumption, escalation of intake, and motivation to obtain heroin were identified. Tom1, a microglial component, was implicated for nociception. Several genes involved in dopaminergic signaling, neuroplasticity and substance use disorders, including Brwd1, Pcp4, Phb1l2 and Mmp15 were implicated for the heroin traits. Additionally, an OUD vulnerable phenotype was associated with genetic variants for consumption and break point, suggesting a specific genetic contribution for OUD-like traits contributing to vulnerability. Together, these findings identify novel genetic markers related to the susceptibility to OUD-relevant behaviors in HS rats. Show less

Protein lysine methacrylation (Kmea) is a recently identified post-translational modification whose biofunction remains poorly understood. Until now, there has been no chemical labeling method for Kmea modification, which has severely hindered the discovery and functional studies of methacrylated proteins. Here, we developed a photocatalytic thia-Michael reaction system for the chemoselective labeling of protein methacrylation. By exploiting the dual effect of steric hindrance and the stability of the generated C-center radical, the reaction interference of the structural isomer crotonylation can be efficiently avoided. Based on this reaction, a multifunctional water-soluble benzenethiol-azide probe azDSH was designed and synthesized, and a workflow for the specific labeling, enrichment, and identification of Kmea proteins was developed. Proteomic identification of histone and nuclear protein extracts and whole-cell lysate revealed a number of novel Kmea proteins and modification sites besides histones, such as HMGB1, TdIF2, UHRF1, HNRPD, BRWD1, TAF1, TACC1, and SETD3, providing new targets for the study of epigenetic regulation. This study provides an effective method for the analysis of protein methacrylation modifications in biological systems. Show less

Identification of large scale structural polymorphisms (copy number variations [CNVs]) of more than 50 bp between the individuals of a species would help in knowing genetic diversity, phenotypic variability, adaptability to tropical environment and disease resistance. Read depth-based method implemented in CNVnator was used for calling copy number variant regions on sequenced data obtained from whole-genome sequencing from 15 pooled samples belonging to five draught cattle breeds of Tamil Nadu. A total of 11,605 CNV regions (CNVRs) were observed covering a genome size of 18.63 percent. Among these, 11,459 were restricted to autosomes, consisting of 11,013 deletions, 353 duplications and 93 complex events. These CNVRs were annotated to 4,989 candidate genes. A total of 8,291 numbers of CNVRs were shared among the five cattle breeds as also supported by principal component analysis and STRUCTURE analyses and 1,172 CNVRs were breed-specific. Four out of five selected breed-specific CNVRs were validated using real-time polymerase chain reaction. Genes with CNVRs are related to milk production (BTN1A1, ABCA1, and LAP3), disease resistance (TLR4 and DNAH8), adaptability (SOD1, CAST, and SMARCAL1), growth (EGFR, NKAIN3), reproduction (BRWD1 and PDE6D), meat and carcass traits (MAP3K5 and NCAM1) and exterior (ATRN and MITF) traits. Gene enrichment analysis based on the gene list retrieved from the CNVRs disclosed over-represented terms (p<0.01) associated with milk fat production. NETWORK analysis had identified 13 putative candidate genes involved in milk fat percentage, milk fat yield, lactation persistency, milk yield, heat tolerance, calving ease, growth and conformation traits. The genome-wide CNVRs identified in the present study produced genomewide partial CNV map in indigenous cattle breeds of Tamil Nadu. Show less

Lymphocyte development consists of sequential and mutually exclusive cell states of proliferative selection and antigen receptor gene recombination. Transitions between each state require large, coordinated changes in epigenetic landscapes and transcriptional programs. How this occurs remains unclear. Here we demonstrate that in small pre-B cells, the lineage and stage-specific epigenetic reader bromodomain and WD repeat-containing protein 1 (BRWD1) reorders three-dimensional chromatin topology to affect the transition between proliferative and gene recombination molecular programs. BRWD1 regulated the switch between poised and active enhancers interacting with promoters, and coordinated this switch with Igk locus contraction. BRWD1 did so by converting chromatin-bound static to dynamic cohesin competent to mediate long-range looping. ATP-depletion revealed cohesin conversion to be the main energetic mechanism dictating dynamic chromatin looping. Our findings provide a new mechanism of cohesin regulation and reveal how cohesin function can be dictated by lineage contextual mechanisms to facilitate specific cell fate transitions. Show less

Kashmir cattle, which were kept by local pastoralists for centuries, are exceptionally resilient and adaptive to harsh environments. Despite its significance, the genomic characteristics of this cattle breed remain elusive. This study utilized whole genome sequences of Kashmir cattle (n = 20; newly sequenced) alongside published whole genomes of 32 distinct breeds and seven core cattle populations (n = 135). The analysis identified ~25.87 million biallelic single nucleotide polymorphisms in Kashmir cattle, predominantly in intergenic and intron regions. Population structure analyses revealed distinct clustering patterns of Kashmir cattle with proximity to the South Asian, African and Chinese indicine cattle populations. Genetic diversity analysis of Kashmir cattle demonstrated lower inbreeding and greater nucleotide diversity than analyzed global breeds. Homozygosity runs indicated less consanguineous mating in Kashmir cattle compared with European taurine breeds. Furthermore, six selection sweep detection methods were used within Kashmir cattle and other cattle populations to identify genes associated with vital traits, including immunity (BOLA-DQA5, BOLA-DQB, TNFAIP8L, FCRL4, AOAH, HIF1AN, FBXL3, MPEG1, CDC40, etc.), reproduction (GOLGA4, BRWD1, OSBP2, LEO1 ADCY5, etc.), growth (ADPRHL1, NRG2, TCF12, TMOD4, GBP4, IGF2, RSPO3, SCD, etc.), milk composition (MRPS30 and CSF1) and high-altitude adaptation (EDNRA, ITPR2, AGBL4 and SCG3). These findings provide essential genetic insights into the characteristics and establish the foundation for the scientific conservation and utilization of Kashmir cattle breed. Show less

Substantial shifts in reproductive behaviors have recently taken place in many high-income countries including earlier age at menarche, advanced age at childbearing, rising childlessness and a lower number of children. As reproduction shifts to later ages, genetic factors may become increasingly important. Although monogenic genetic effects are known, the genetics underlying human reproductive traits are complex, with both causal effects and statistical bias often confounded by socioeconomic factors. Here, we review genome-wide association studies (GWASs) of 44 reproductive traits of both female and male individuals from 2007 to early 2024, examining reproductive behavior, reproductive lifespan and aging, infertility and hormonal concentration. Using the GWAS Catalog as a basis, from 159 relevant studies, we isolate 37 genes that harbor association signals for four or more reproductive traits, more than half of which are linked to rare Mendelian disorders, including ten genes linked to reproductive-related disorders: FSHB, MCM8, DNAH2, WNT4, ESR1, IGSF1, THRB, BRWD1, CYP19A1 and PTPRF. We also review the relationship of reproductive genetics to related health and behavioral traits, aging and longevity and the effect of parental age on offspring outcomes as well as reflecting on limitations, open questions and challenges in this fast-moving field. Show less

The BRCA1/2 mutation status testing is the global standard of care for breast cancer patients with a family history of cancer. BRCA1/2 mutations are known to be ethno-specific. For some ethnic groups of the Northern Asia (Buryats, Yakuts, Altaians, Tuvans, Khakasses, etc.) the founder mutations in the BRCA1/2 genes have not been revealed. This systematic review was conducted to assess the prevalence of BRCA1/2 mutation in breast cancer patients inhabiting Eastern Europe and Northern Asia (or Siberia). A total of 23,561 studies published between 2014 and 2024 were analyzed, of which 55 were included in the review. The literature search was conducted using RusMed, Cyberleninka, Google Scholar, eLibrary, NCBI databases (n=5) and conference papers. The founder mutations (c.5266dupC and/or c.181T>G) of BRCA1 gene that were frequently observed in the Slav peoples were also identified in Chechens, Armenians, Bashkirs, Ukrainians, Mordovians, Mari, Kabardians, Tatars, Uzbeks, Kyrgyz, Ossetians, Khanty indigenous peoples and Adygs. For Chechens, Kabardians, Ingush, Buryats, Khakasses, Sakha, Tuvans and Armenians, rare pathogenic variants of the BRCA1/2, ATM, СНЕК2, BRIP1, NBN, PTEN, TP53, PMS1, XPA, LGR4, BRWD1 and PALB2 genes were found. No data are available about the frequency of pathogenic BRCA1/2 mutations for ethnic groups, such as the Udmurts, Komi, Tajiks, Tabasarans, and Nogais indigenous people. This is the first systematic review that provides the spectrum of BRCA mutations in ethnic groups of breast cancer patients inhabiting Eastern Europe and Northern Asia. It has been shown that the mutations are ethnospecific (varied widely within groups) and not all groups are equally well studied. Further studies on the ethnic specificity of BRCA gene mutations are required. Show less

Whole exome sequencing of peripheral blood samples from Tuvan females diagnosed with breast and ovarian cancers (BC/OC) was performed to search for new genes involved in BC/OC pathogenesis. Considering the high cost of whole exome sequencing and study material requirements, 9 samples were selected from 61 genomic DNA samples. A mutation in the LGR4 gene (rs34804482) involved in the tumor-mediated Wnt signaling pathway and a mutation in the BRWD1 gene (rs147211854) involved in chromatin remodeling were identified in BC patients. A mutation in the CITED2 gene (rs77963348) involved in the pathogenesis of primary ovarian insufficiency was identified in a patient with OC and a history of infertility. A mutation in the PDGFRA gene (rs2291591) was identified in two BC/OC patients. LRG4, BRWD1, PDGFRA, and CITED2 germline pathogenic mutations were discovered in Tuvan women diagnosed with BC/OC for the first time. Show less

The increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing toward vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct OUD behaviors while maintaining a uniform environment, an experimental design not easily achieved in humans. Furthermore, we used a novel non-linear network-based clustering approach to characterize rats based on OUD vulnerability to assess genetic variants associated with OUD susceptibility. Our findings confirm the heritability of several OUD-like behaviors, including OUD susceptibility. Additionally, several genetic variants associated with nociceptive threshold prior to heroin experience, heroin consumption, escalation of intake, and motivation to obtain heroin were identified. Tom1, a microglial component, was implicated for nociception. Several genes involved in dopaminergic signaling, neuroplasticity and substance use disorders, including Brwd1, Pcp4, Phb1l2 and Mmp15 were implicated for the heroin traits. Additionally, an OUD vulnerable phenotype was associated with genetic variants for consumption and break point, suggesting a specific genetic contribution for OUD-like traits contributing to vulnerability. Together, these findings identify novel genetic markers related to the susceptibility to OUD-relevant behaviors in HS rats. Show less

Germinal center (GC) B cells segregate into three subsets that compartmentalize the antagonistic molecular programs of selection, proliferation, and somatic hypermutation. In bone marrow, the epigenetic reader BRWD1 orchestrates and insulates the sequential stages of cell proliferation and Show less

As a subgroup of lung cancer, small cell lung cancer (SCLC) is characterized by a short tumor doubling time, high rates of early occurred distant cancer spread and poor outcomes. Our study aimed to identify novel molecular markers associated with SCLC prognosis. Microarray data from the Gene Expression Omnibus (GEO) database of SCLC tumors and paired normal tissues were obtained. In the dataset, Differentially expressed genes (DEGs) which were identified by comparing gene expression between normal lung and SCLC samples, were screened using the R language. The STRING database was used to map protein-protein interaction (PPI) networks, and these were visualized with the Cytoscape software. Go enrichment analysis and prediction were performed using the Metascape database and the results were visualized. Autophagy-related prognostic genes were identified by univariate COX regression analysis. Subsequently, stepwise model selection using the Akaike information criterion (AIC) and multivariate COX regression model was performed to construct DEGs signature. Survival receiver operating characteristic (ROC) analysis was used to assess the performance of survival prediction. At last, we evaluated the differences in drug sensitivity of the two groups of patients to common chemotherapeutic drugs and small-molecule targeted drugs. A total of 441 identified DE genes, including 412 downregulated and 29 upregulated genes were identified. GO enrichment analyses showed that DEGs were significantly enriched in the collagen-containing extracellular matrix and extracellular matrix organization. 16 genes were individually associated with OS in univariate analyses. The high expression of 6 genes (HIST1H4L, RP11-16O9.2, SNORA71A, SELV, FAM66A and BRWD1-AS1)) was associated with the poor prognosis of SCLC patients. To predict patients' outcomes, we developed an individual's risk score model based on the 6 genes. We found that SCLC patients with a low-risk score had significantly better survival than those with a high-risk score. What's more, association analysis between clinicopathological factors and gene signature showed the risk score was higher in patients with higher clinical stage or T stage. What's more, the patients in the high-risk score group had better treatment effects for etoposide and docetaxel. This suggests that our model can guide clinical treatment decisions. A novel six-gene signature was determined for prognostic prediction in SCLC. Our findings may provide new insights into the precise treatment and prognosis prediction of SCLC. Show less

The prognosis of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) remained unsatisfactory currently, more anti-HER2 agents are needed. Here we report a phase I study that evaluated the safety, activity, and biomarkers of LZM005, a HER2 antibody, used as a monotherapy or in combination with trastuzumab plus docetaxel in patients with HER2-positive MBC. From October 2017 to December 2019, 34 patients received LZM005 (14 monotherapy, 20 combination therapy). No DLT was observed. The common adverse events (AEs) in phase Ia included diarrhea (21.4%), infusion reaction (21.4%), and hypertriglyceridemia (21.4%), while those in phase Ib were leukopenia (85.0%), neutropenia (75.0%), anemia (60.0%), diarrhea (60.0%), and rash/pruritus (50.0%). All AEs were manageable. In phase Ia, partial response (PR) was achieved in one case (1/14, overall response rate [ORR]: 7.1%); the disease control rate was 42.90% (6/14). In phase Ib, 11 patients (55.0%) achieved PR, and eight (40.0%) had stable disease. The ORR was 100% (6/6) in trastuzumab-naive and 35.7% (5/14) in trastuzumab-pretreated patients. Biomarker analysis showed that chromatin remodeling genes KMT2B and BRWD1 were associated with better progression-free survival. LZM005 is well tolerated and shows potent activity in patients with HER2-positive MBC. Show less

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes. Show less

Neurodegenerative diseases such as Alzheimer's disease (AD) are an increasing public health challenge. There is an urgent need to shift the focus to accurate detection of clinical AD at the physical examination stage. The purpose of this study was to identify biomarkers for AD diagnosis. Differential expression analysis was performed on a dataset including prefrontal cortical samples and peripheral blood samples of AD to identify shared differentially expressed genes (DEGs) shared between the two datasets. In addition, a minimum absolute contraction and selection operator (LASSO) model based on shared-DEGs identified nine signature genes (MT1X, IGF1, DLEU7, TRIM36, PTPRC, WNK2, SPG20, C8orf59, and BRWD1) that accurately predict AD occurrence. Enrichment analysis showed that the signature gene was significantly associated with the AD-related p53 signaling pathway, T-cell receptor signaling pathway, HIF-1 signaling pathway, AMPK signaling pathway, and FoxO signaling pathway. Thus, our results identify not only biomarkers for diagnosing AD but also potentially specific pathways. The AD biomarkers proposed in this study could serve as indicators for prevention and diagnosis during physical examination. Show less

Platelet activation is commonly detected after infection by multiple viruses such as human immunodeficiency virus (HIV), H1N1 influenza, Hepatitis C virus (HCV), Ebola virus (EBV), and Dengue virus (DENV). Non-coding RNAs (ncRNAs) constitute the majority of the human transcribed genome, but the biology of platelet ncRNAs is largely unexplored. In this study, we performed microarray profiling to characterize the expression profile of human platelets infected with EBV in vitro after 2 h. A total of 187 long non-coding RNAs (lncRNAs) displayed differences, of which 114 were upregulated and 73 were downregulated; 78 microRNAs (miRNAs) showed differences, including 73 upregulated and 5 downregulated; 808 mRNAs displayed differences, among which 367 were upregulated and 441 were downregulated. Gene ontology (GO) analysis mostly related to G protein-coupled receptor signaling pathway, detection of chemical stimulus involved in sensory perception of smell and regulation of transcription by RNA polymerase II. Pathway analysis showed that the differentially expressed genes were mainly enriched in cell metabolism and immune-related response. A ceRNA network was established based on predicting regulatory pairs in differentially expressed genes, in which hsa-miR-6877-3p had the highest regulatory capability (degree = 31), FAM230A was the lncRNA with the highest regulatory capability (degree = 28). According to the EBV related miRNA regulation network, it revealed that ebv-miR-BART19-3p had the most target genes and BRWD1, FAM126B, TFRC and JMY were the genes most regulated by EBV-related miRNAs. After overlapping the three networks, we found that the EIFAK2 gene was strongly correlated with autologous ncRNAs, including hsa-miR-1972, hsa-miR-504-3p and hsa-miR-6825-5p, as well as with EBV ncRNAs, including EBER1, EBER2, miR-BART7-3p and miR-BART16. The present study contributes to a better understanding of the expression profiling of ncRNAs and their functions in platelets activated by EBV in vitro, and paves the way to further study on platelet function. Show less

Spermatogenesis is driven by an ordered series of events, which rely on trafficking of specific proteins between nucleus and cytoplasm. The karyopherin α family of proteins mediates movement of specific cargo proteins when bound to karyopherin β. Karyopherin α genes have distinct expression patterns in mouse testis, implying they may have unique roles during mammalian spermatogenesis. Here, we use a loss-of-function approach to determine specifically the role of Kpna6 in spermatogenesis and male fertility. We show that ablation of Kpna6 in male mice leads to infertility and has multiple cumulative effects on both germ cells and Sertoli cells. Kpna6-deficient mice exhibit impaired Sertoli cell function, including loss of Sertoli cells and a compromised nuclear localization of the androgen receptor. Furthermore, our data demonstrate devastating defects on spermiogenesis, including incomplete sperm maturation and a massive reduction in sperm number, accompanied by disturbed histone-protamine exchange, differential localization of the transcriptional regulator BRWD1 and altered expression of RFX2 target genes. Our work uncovers an essential role of Kpna6 in spermatogenesis and, hence, in male fertility. Show less

Circular RNAs (circRNAs) can act as vital players in osteoarthritis (OA). However, the roles of circRNAs in OA remain obscure. Herein, we explored the roles of exosomal circRNA bromodomain and WD repeat domain containing 1(circ-BRWD1) in OA pathology. In vitro model of OA was constructed by treating CHON-001 cells with interleukin-1β (IL-1β). Quantitative real-time polymerase chain reaction (qRT-PCR) assay was used for circ-BRWD1, BRWD, miR-1277, and TNF receptor-associated factor 6 (TRAF6) levels. RNase R assay was conducted for the feature of circ-BRWD1. Transmission electron microscopy (TEM) was employed to analyze the morphology of exosomes. Western blot assay was performed for protein levels. Cell Counting Kit-8 (CCK-8) assay, flow cytometry analysis, and 5-Ethynyl-2'-deoxyuridine (EDU) assay were adopted for cell viability, apoptosis, and proliferation, respectively. Enzyme-linked immunosorbent assay (ELISA) was carried out for the concentrations of interleukin-6 (IL-6) and interleukin-8 (IL-8). Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to analyze the interaction between miR-1277 and circ-BRWD1 or TRAF6. Circ-BRWD1 was increased in OA cartilage tissues, IL-1β-treated CHON-001 cells, and the exosomes derived from IL-1β-treated CHON-001 cells. Exosome treatment elevated circ-BRWD1 level, while exosome blocker reduced circ-BRWD1 level in IL-1β-treated CHON-001 cells. Silencing of circ-BRWD1 promoted cell viability and proliferation and repressed apoptosis, inflammation, and extracellular matrix (ECM) degradation in IL-1β-stimulated CHON-001 cells. For mechanism analysis, circ-BRWD1 could serve as the sponge for miR-1277 to positively regulate TRAF6 expression. Moreover, miR-1277 inhibition ameliorated the effects of circ-BRWD1 knockdown on IL-1β-mediated CHON-001 cell damage. Additionally, miR-1277 overexpression relieved IL-1β-induced CHON-001 cell injury, while TRAF6 elevation restored the impact. Exosomal circ-BRWD1 promoted IL-1β-induced CHON-001 cell progression by regulating miR-1277/TRAF6 axis. Show less

Genetics-associated asthenoteratozoospermia is often seen in patients with multiple morphological abnormalities of the sperm flagella (MMAF). Although 24 causative genes have been identified, these explain only approximately half of patients with MMAF. Since sperm flagella and motile cilia (especially respiratory cilia) have similar axonemal structures, many patients with MMAF also exhibit respiratory symptoms, such as recurrent airway infection, chronic sinusitis, and bronchiectasis, which are frequently associated with primary ciliary dyskinesia (PCD), another recessive disorder. Here, exome sequencing was conducted to evaluate the genetic cause in 53 patients with MMAF and classic PCD/PCD-like symptoms. Two homozygous missense variants and a compound-heterozygous variant in the BRWD1 gene were identified in three unrelated individuals. BRWD1 staining was detected in the whole flagella and respiratory cilia of normal controls but was absent in BRWD1-mutated individuals. Transmission electron microscopy and immunostaining demonstrated that BRWD1 deficiency in human affected respiratory cilia and sperm flagella differently, as the absence of outer and inner dynein arms in sperm flagellum and respiratory cilia, while with a decreased number and outer doublet microtubule defects of respiratory cilia. To our knowledge, this is the first report of a BRWD1-variant-related disease in humans, manifesting as an autosomal recessive form of MMAF and PCD/PCD-like symptoms. Our data provide a basis for further exploring the molecular mechanism of BRWD1 gene during spermatogenesis and ciliogenesis. Show less

BACKGROUND Alzheimer disease (AD) is a typical progressive and destructive neurodegenerative disease that has been studied extensively. However, genetic features and molecular mechanisms underlying AD remain unclear. Here we used bioinformatics to investigate the candidate nuclear genes involved in the molecular mechanisms of AD. MATERIAL AND METHODS First, we used Gene Expression Omnibus (GEO) database to obtain the expression profiles of the mRNAs from hippocampus microarray and identify differentially expressed genes (DEGs) the plier algorithm. Second, functional annotation and visualization of the DEGs were conducted by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Finally, BioGRID, IntAct, STRING, and Cytoscape were utilized to construct a protein-protein interaction (PPI) network. Hub genes were analytically obtained from the PPI network and the microRNA (miRNA)-target network. RESULTS Two hippocampus microarrays (GSE5281 and GSE48350) were obtained from the GEO database, comprising 161 and 253 cases separately. Among these, 118 upregulated genes and 694 downregulated genes were identified. The upregulated DEGs were mainly involved in positive regulation of transcription from RNA polymerase II promoter, positive regulation of cartilage development, and response to wounding. The downregulated DEGs were enriched in chemical synaptic transmission, neurotransmitter secretion, and learning. By combining the results of PPI and miRNA-target network, 8 genes and 2 hub miRNAs were identified, including YWHAZ, DLG4, AGAP2, EGFR, TGFBR3, PSD3, RDX, BRWD1, and hsa-miR-106b-5p and hsa-miR-93-5p. These target genes are highly enriched in various key pathways, such as amyloid-beta formation, regulation of cardiocyte differentiation, and actin cytoskeleton reorganization. CONCLUSIONS In this study, YWHAZ, DLG4, AGAP2, EGFR, TGFBR3, PSD3, RDX, and BRWD1 were identified as candidate genes for future molecular studies in AD, which is expected to improve our understanding of its cause and potential molecular mechanisms. Nuclear genes, DEGs, and related networks identified by integrated bioinformatics analysis may serve as diagnostic and therapeutic targets for AD. Show less

Heat stress negatively impacts the reproductive performance of dairy cows. The main objective of this study was to dissect the genetic basis underlying dairy cow fertility under heat stress conditions. Our first goal was to estimate genetic components of cow conception across lactations considering heat stress. Our second goal was to reveal individual genes and functional gene-sets that explain a cow's ability to conceive under thermal stress. Data consisted of 74 221 insemination records on 13 704 Holstein cows. Multitrait linear repeatability test-day models with random regressions on a function of temperature-humidity index values were used for the analyses. Heritability estimates for cow conception under heat stress were around 2-3%, whereas genetic correlations between general and thermotolerance additive genetic effects were negative and ranged between -0.35 and -0.82, indicating an unfavorable relationship between cows' ability to conceive under thermo-neutral vs. thermo-stress conditions. Whole-genome scans identified at least six genomic regions on BTA1, BTA10, BTA11, BTA17, BTA21 and BTA23 associated with conception under thermal stress. These regions harbor candidate genes such as BRWD1, EXD2, ADAM20, EPAS1, TAOK3, and NOS1, which are directly implicated in reproductive functions and cellular response to heat stress. The gene-set enrichment analysis revealed functional terms related to fertilization, developmental biology, heat shock proteins and oxidative stress, among others. Overall, our findings contribute to a better understanding of the genetics underlying the reproductive performance of dairy cattle under heat stress conditions and point out novel genomic strategies for improving thermotolerance and fertility via marker-assisted breeding. Show less

We aimed to identify potential mechanism associated with acute kidney injury (AKI) after kidney transplantation. The dataset GSE53771, which contained 18 zero-hour (ZERO group) and 18 selected post-transplant (POST group) biopsy samples from 18 kidney allografts (8 AKI and 10 controls) was downloaded from GEO database. Differentially expressed miRNAs (DEMIs) were screened using limma package, and bidirectional hierarchical clustering of the DEMIs was performed using the pheatmap package. Target genes of DEMIs were predicted by miRWalk 2.0, miRNA-target genes networks were presented using Cytoscape, protein-protein interaction (PPI) networks were constructed by STRING (version:10.0) database, and competing endogenous RNAs (ceRNA) regulating network were constructed using Cytoscape. In ZERO and POST groups, a total of 4 and 24 differentially expressed miRNAs were obtained in AKI samples compared with control, respectively. Specifically, 71 lncRNAs were obtained to interact with five miRNAs (hsa-miR-215-5p, hsa-miR-192-5p, hsa-miR-422a, hsa-miR-212-3p and hsa-miR-122-5p). Histone chaperone ASF1A (ASF1A) and bromodomain and WD repeat-containing protein 1(BRWD1) were targeted by hsa-miR-212-3p in PPI network. In ceRNA network, lncRNA XIST could interact with four miRNAs (hsa-miR-212-3p, hsa-miR-122-5p, hsa-miR-215-5p, and hsa-miR-192-5p). LncRNA XIST might serve as a ceRNA to sponge hsa-miR-212-3p to regulate the development of AKI via altering the expression of ASF1A/BRWD1. Furthermore, lncRNA XIST could also interact with hsa-miR-122-5p to modulate the expression of PFKFB2 in thyroid hormone signaling pathway and AMPK signaling pathway. LncRNA XIST can serve as a ceRNA to sponge hsa-miR-212-3p and hsa-miR-122-5p to regulate AKI progression via modulating the expression of ASF1A, BRWD1, and PFKFB2.[Figure: see text]. Show less

Currently, brown adipose tissue (BAT) is a therapeutic target in obesity and diabetes, but the mechanism of BAT activation remains unclear. Because increasing emphasis has been placed on the role of intracellular peptides in biological processes, we conducted a study to gain insight into the mechanism of BAT activation by using a peptidomic approach and then attempted to identify peptides that are capable of activating BAT. In the present study, we generated the peptidomic profile of the intracellular peptides in brown adipocytes treated with forskolin (FSK) using a peptidomic approach. Then, the differentially expressed peptides were evaluated via Gene Ontology (GO) enrichment, KEGG pathway, and protein-protein interaction (PPI) network analysis. Finally, we selected candidate peptides for further validation via assessing the expression levels of UCP-1 and PGC-1α in brown adipocytes exposed to the peptides. A total of 4,370 peptides were identified, of which 951 were upregulated and 379 were downregulated after FSK treatment. Bioinformatic analysis demonstrated that the ECM-receptor interaction GO term was the most enriched and that collagen alpha-related proteins exhibited the highest degree of PPI. Four peptides separately derived from TSC22 domain family protein 1 (T22D1), bromodomain and WD repeat-containing protein 1 (BRWD1), protein piccolo (PCLO), and collagen alpha-1 (III) chain (CO3A1) increased the expression levels of UCP-1 and PGC-1α. ECM-receptor interaction may play an important role in the process of FSK-stimulated BAT activation, and the pT22D1tide, pBRWD1tide, pPCLOtide, and pCO3A1tide peptides potentially promote BAT thermogenesis. Show less

To investigate the role of MALAT1 in the cisplatin treatment of cervical cancer and its underlying mechanism. The effects of different doses of cisplatin on the proliferation and apoptosis of cervical cancer cells were detected by cell counting kit-8 (CCK-8) assay and apoptosis assay, respectively. We used bioinformatics methods to predict the downstream genes of MALAT1 and examined the expression relationship between the target gene BRWD1 and MALAT1 by quantitative Real-time polymerase chain reaction (qRT-PCR). Western blot was performed to detect the expression levels of apoptosis-related proteins and key genes in PI3K/AKT signaling pathway. After MALAT1 was knocked down, cisplatin showed an inhibited effect on the proliferation of HeLa and C-33A cells in a concentration-dependent manner. After treatment of cervical cancer cells with 5 μM cisplatin, MALAT1 knockdown enhanced the apoptosis of HeLa and C-33A cells, and up-regulated expression of cleaved caspase-3. Over-expression of MALAT1 in cells showed the opposite results. Starbase website was used to predict that MALAT1 might regulate BRWD1 expression. Over-expression of MALAT1 significantly up-regulated the mRNA expression of BRWD1 in HeLa and C-33A cells. After knockdown of BRWD1, cisplatin markedly decreased the proliferation of HeLa and C-33A cells, and promoted cell apoptosis and cleaved caspase-3 expression. Besides, HeLa and C-33A cells showed increased expressions of p-PI3K and p-AKT after MALAT1 was up-regulated. MALAT1 promoted the cisplatin resistance of cervical cancer, which might be related to regulation of cell apoptosis via BRWD1 and PI3K/AKT pathway. Show less

Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. Here we show that in small pre-B cells, the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 regulates over 7000 genes to repress proliferative and induce differentiation programs. However, BRWD1 does not regulate the expression of TFs required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations have B-cell transcriptional profiles and enhancer landscapes similar to those observed in Brwd1 Show less

Non-obstructive azoospermia (NOA), a severe form of male infertility, is often suspected to be linked to currently undefined genetic abnormalities. To explore the genetic basis of this condition, we successfully sequenced ~650 infertility-related genes in 757 NOA patients and 709 fertile males. We evaluated the contributions of rare variants to the etiology of NOA by identifying individual genes showing nominal associations and testing the genetic burden of a given biological process as a whole. We found a significant excess of rare, non-silent variants in genes that are key epigenetic regulators of spermatogenesis, such as BRWD1, DNMT1, DNMT3B, RNF17, UBR2, USP1 and USP26, in NOA patients (P = 5.5 × 10(-7)), corresponding to a carrier frequency of 22.5% of patients and 13.7% of controls (P = 1.4 × 10(-5)). An accumulation of low-frequency variants was also identified in additional epigenetic genes (BRDT and MTHFR). Our study suggested the potential associations of genetic defects in genes that are epigenetic regulators with spermatogenic failure in human. Show less

B lymphopoiesis requires that immunoglobulin genes be accessible to RAG1-RAG2 recombinase. However, the RAG proteins bind widely to open chromatin, which suggests that additional mechanisms must restrict RAG-mediated DNA cleavage. Here we show that developmental downregulation of interleukin 7 (IL-7)-receptor signaling in small pre-B cells induced expression of the bromodomain-family member BRWD1, which was recruited to a specific epigenetic landscape at Igk dictated by pre-B cell receptor (pre-BCR)-dependent Erk activation. BRWD1 enhanced RAG recruitment, increased gene accessibility and positioned nucleosomes 5' to each Jκ recombination signal sequence. BRWD1 thus targets recombination to Igk and places recombination within the context of signaling cascades that control B cell development. Our findings represent a paradigm in which, at any particular antigen-receptor locus, specialized mechanisms enforce lineage- and stage-specific recombination. Show less

Postmeiotic gene expression is essential for development and maturation of sperm and eggs. We report that the dual bromodomain-containing protein BRWD1, which is essential for both male and female fertility, promotes haploid spermatid-specific transcription but has distinct roles in oocyte meiotic progression. Brwd1 deficiency caused down-regulation of ∼300 mostly spermatid-specific transcripts in testis, including nearly complete elimination of those encoding the protamines and transition proteins, but was not associated with global epigenetic changes in chromatin, which suggests that BRWD1 acts selectively. In females, Brwd1 ablation caused severe chromosome condensation and structural defects associated with abnormal telomere structure but only minor changes in gene expression at the germinal vesicle stage, including more than twofold overexpression of the histone methyltransferase MLL5 and LINE-1 elements transposons. Thus, loss of BRWD1 function interferes with the completion of oogenesis and spermatogenesis through sexually dimorphic mechanisms: it is essential in females for epigenetic control of meiotic chromosome stability and in males for haploid gene transcription during postmeiotic sperm differentiation. Show less