Association of CDH11 with Autism Spectrum Disorder Revealed by Matched-gene Co-expression Analysis and Mouse Behavioral Studies / 神经科学通报·英文版

A large number of putative risk genes for autism spectrum disorder (ASD) have been reported. The functions of most of these susceptibility genes in developing brains remain unknown, and causal relationships between their variation and autism traits have not been established. The aim of this study was to predict putative risk genes at the whole-genome level based on the analysis of gene co-expression with a group of high-confidence ASD risk genes (hcASDs). The results showed that three gene features - gene size, mRNA abundance, and guanine-cytosine content - affect the genome-wide co-expression profiles of hcASDs. To circumvent the interference of these features in gene co-expression analysis, we developed a method to determine whether a gene is significantly co-expressed with hcASDs by statistically comparing the co-expression profile of this gene with hcASDs to that of this gene with permuted gene sets of feature-matched genes. This method is referred to as "matched-gene co-expression analysis" (MGCA). With MGCA, we demonstrated the convergence in developmental expression profiles of hcASDs and improved the efficacy of risk gene prediction. The results of analysis of two recently-reported ASD candidate genes, CDH11 and CDH9, suggested the involvement of CDH11, but not CDH9, in ASD. Consistent with this prediction, behavioral studies showed that Cdh11-null mice, but not Cdh9-null mice, have multiple autism-like behavioral alterations. This study highlights the power of MGCA in revealing ASD-associated genes and the potential role of CDH11 in ASD.

Differential mRNA expression in C57BL/6 mice with bleomycin-induced pulmonary fibrosis and its association with LncRNA co-expression network / 南方医科大学学报

OBJECTIVE@#To study the changes in mRNA and long non-coding RNA (lncRNA) expression profiles in a mouse model of bleomycin-induced lung fibrosis and identify lung fibrosis-related mRNA for coding-noncoding coexpression (CNC) bioinformatics analysis of the differential lncRNAs.@*METHODS@#Lung fibrosis was induced by intratracheal injection of bleomycin in 10 C57BL/6 mice and another 10 mice with intratracheal injection of saline served as the control group. Lung tissues were harvested from the mice at 14 days after the injections and lung fibrosis was assessed using Masson and HE staining. LncRNA chip technology was used to screen the differentially expressed mRNAs and lncRNAs in mice with lung fibrosis, and GO and KEGG pathway analyses of the differential mRNAs were performed using NCBI database and UCSC database to identify possible fibrosis-related mRNAs, which were validated by qRT-PCR to construct a coding and non-coding co- expression network with the differential lncRNAs.@*RESULTS@#Compared with the control mice, the mice with intratracheal injection of bleomycin showed obvious lung fibrosis. The results of gene chip analysis showed that 127 mRNAs were upregulated and 184 mRNAs were down-regulated in the model group as compared with the control group. GO and pathway analysis suggested that the differentially expressed genes participated mainly in immune response, cell differentiation, and cytoskeletons; the involved signal pathways were associated mainly with cytokine and cytokine receptor interaction and chemokine signal transduction. Bioinformatics analysis identified a significant coexpression network between the fibrosisrelated mRNA and the differentially expressed lncRNA.@*CONCLUSIONS@#In mice with lung fibrosis, the differential expressions of fibrosis-related mRNAs in the lung tissues are closely correlated with the co- expressions of a large number of differential lncRNAs, which points to a new direction for investigation of the pathogenesis of pulmonary fibrosis.

Genetic variation of aggrecanase-2 (ADAMTS5) in susceptibility to osteoarthritis

Aggrecanase-2 (ADAMTS5) gene is responsible for aggrecan degradation that may contribute to cartilage destruction in a mouse osteoarthritis (OA) model. We aimed to investigate the effects of ADAMTS5 gene polymorphisms on OA risk in a Chinese population. A total of 300 OA patients and 300 controls were recruited and their genotypes for ADAMTS5 gene rs226794 and rs2830585 polymorphisms were determined using a custom-by-design 48-Plex single nucleotide polymorphism Scan™ kit. ADAMTS5-associated genes were identified by co-expression analysis and their functions were investigated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Bioinformatics analysis showed that ADAMTS5 was significantly related to the components, structural constituent, and organization of the extracellular matrix. The rs2830585 polymorphism, but not rs226794 polymorphism, was significantly associated with an increased risk of knee OA. Stratified analysis further confirmed this significant association in patients at age ≥55 years. In conclusion, the ADAMTS5 rs2830585 polymorphism may be involved in the development of knee OA by destroying the extracellular matrix, but this finding should be further confirmed by larger studies.

Microarray Profiling and Co-Expression Analysis of Long Noncoding RNA and Apoptosis-Associated mRNA in Mouse Intestinal Mucosa Following IntestinalI schemia/Reperfusion Injury / 中山大学学报(医学科学版)

@#【Objective】To investigate the lncRNA expression profile and potential roles in mouse intestinal mucosa after I/R treatment and explore the co-expression relationship between dysregulated lncRNA and apoptotic mRNA at the early stage of reperfusion. 【Methods】 The expression profiles of lncRNA were obtained using microarray and some lncRNA were further validated by quantitative real- time polymerase chain reaction （qRT- PCR）. Gene ontology（GO）analyses were performed to determine closely related biological functions，especially apoptosis-related functions. Finally， the known apoptosis- related mRNA with obviously changes were selected to construct the co-expression network of the dysregulated lncRNA and their correlated apoptotic mRNA， and were analyzed by CNC analysis to calculate the significant correlation of IncRNA-mRNA pairs.【Results】Compared with sham operation group，the expression profile of lncRNA in intestinal epithelium of mice after intestinal I/R was significantly changed ，including 1 503 up- regulated lncRNAs and 2 099 down- regulated lncRNA （Fold change≥2，P<0.05）. At the same time，1 528 mRNA were up- regulated in I/R group，while 1 630 mRNA were down- regulated（fold change≥2.0，P<0.05）. GO enrichment analysis showed that the main functions involved in regulation were lipid metabolism，redox reaction，stress reaction，apoptosis process，programmed cell death，cell cycle，inflammatory response，endothelial cell differentiation and proliferation， tissue remodeling，MAPK，Wnt，vascular endothelial growth factor signaling pathway and so on. Apoptosis-related subitems were enriched in the up- and down-regulated annotations of GO molecular function in different forms ，which were in the forefront. There was a significant co-expression relationship between apoptosis- related mRNA and dysregulated lncRNA. 【Conclusion】 In this study，we established and preliminarily validated the expression profiles of the differentially expressed lncRNA at the early stage of reperfusion in mouse intestinal ischemia injury. Bioinformatics analysis showed that the important biological function of dysregulated lncRNA was the regulation of apoptosis-related processes，and a large number of those lncRNA were indeed highly coexpressed with apoptotic genes ，which would provide a basis and direction for future research.