RESUMO
Genetic sequencing has identified high-confidence ASD risk genes with loss-of-function mutations. How the haploinsufficiency of distinct ASD risk genes causes ASD remains to be elucidated. In this study, we examined the role of four top-ranking ASD risk genes, ADNP, KDM6B, CHD2, and MED13, in gene expression regulation. ChIP-seq analysis reveals that gene targets with the binding of these ASD risk genes at promoters are enriched in RNA processing and DNA repair. Many of these targets are found in ASD gene database (SFARI), and are involved in transcription regulation and chromatin remodeling. Common gene targets of these ASD risk genes include a network of high confidence ASD genes associated with gene expression regulation, such as CTNNB1 and SMARCA4. We further directly examined the transcriptional impact of the deficiency of these ASD risk genes. Our mRNA profiling with qPCR assays in cells with the knockdown of Adnp, Kdm6b, Chd2 or Med13 has revealed an intricate pattern of their cross-regulation, as well as their influence on the expression of other ASD genes. In addition, some synaptic genes, such as Snap25 and Nrxn1, are strongly regulated by deficiency of the four ASD risk genes, which could be through the direct binding at promoters or indirectly through the targets like Ctnnb1 or Smarca4. The identification of convergent and divergent gene targets that are regulated by multiple ASD risk genes will help to understand the molecular mechanisms underlying common and unique phenotypes associated with haploinsufficiency of ASD-associated genes.
Assuntos
Transtorno do Espectro Autista , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , Transtorno do Espectro Autista/genética , Regulação da Expressão Gênica/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , beta Catenina/genética , beta Catenina/metabolismo , DNA Helicases/genética , Haploinsuficiência/genética , Complexo Mediador/genética , Complexo Mediador/metabolismo , Proteínas de Ligação a DNA/genética , Regiões Promotoras Genéticas/genética , Proteínas Nucleares/genética , Proteínas do Tecido Nervoso/genéticaRESUMO
The evidence remains inconsistent regarding whether vitamin D deficiency (VDD) increases the risk of prediabetes. This study aimed to examine whether there is sex-specific association between VDD and impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) in Henan. The data were sourced from the survey of chronic diseases and nutrition in Henan. Multinomial logistic regression models based on complex sampling design and weight were developed to estimate the odds ratio (OR) and confidence interval (95%CI) for measuring the association between VDD and IFG/IGT. The prevalence rate of IGT in men was 20.1% in the VDD group, significantly higher than that in the non-VDD group (10.5%), but no significant difference was observed in women between the VDD and non-VDD groups; there were no significant differences in IFG prevalence between the VDD and non-VDD groups in either men or women. It was found that the association between VDD and IGT was statistically significant in men. The adjusted OR (95%CI) of VDD was 1.99 (1.24-3.19) for IGT in men and 14.84 (4.14-53.20) for IGT in men having a family history of DM. Thus, men with VDD were more likely to live with IGT than those without VDD, especially for men having a family history of diabetes.
Assuntos
Intolerância à Glucose , Fenótipo , Estado Pré-Diabético , Deficiência de Vitamina D , Humanos , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/sangue , Masculino , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/sangue , Feminino , China/epidemiologia , Pessoa de Meia-Idade , Adulto , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/sangue , Prevalência , Fatores de Risco , Glicemia/metabolismo , Glicemia/análise , Fatores Sexuais , Idoso , Modelos Logísticos , Estudos Transversais , Razão de ChancesRESUMO
Podocytes are particularly sensitive to lipid accumulation, which has recently emerged as a crucial pathological process in the progression of proteinuric kidney diseases like diabetic kidney disease and focal segmental glomerulosclerosis. However, the underlying mechanism remains unclear. Here, podocytes predominantly expressed protein dedicator of cytokinesis 5 (Dock5) is screened to be critically related to podocyte lipid lipotoxicity. Its expression is reduced in both proteinuric kidney disease patients and mouse models. Podocyte-specific deficiency of Dock5 exacerbated podocyte injury and glomeruli pathology in proteinuric kidney disease, which is mainly through modulating fatty acid uptake by the liver X receptor α (LXRα)/scavenger receptor class B (CD36) signaling pathway. Specifically, Dock5 deficiency enhanced CD36-mediated fatty acid uptake of podocytes via upregulating LXRα in an m6 A-dependent way. Moreover, the rescue of Dock5 expression ameliorated podocyte injury and proteinuric kidney disease. Thus, the findings suggest that Dock5 deficiency is a critical contributor to podocyte lipotoxicity and may serve as a promising therapeutic target in proteinuric kidney diseases.