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Differential Expression of Nuclear Receptors and Coregulators in Human Brain Tissues from Autistic Individuals versus Controls Open Access

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders that are characterized by impaired reciprocal social interactions, delayed or aberrant communication, and stereotyped, repetitive behaviors, often with restricted interests. Many causes of autism have been proposed, and genetic factors may be the most significant cause for this disease. Although many candidate genes have been proposed on the basis of genetic studies, previous studies from our laboratory based on gene expression profiling demonstrated that retinoic acid-related orphan receptor-alpha (RORA) and many other nuclear receptor and coregulator genes were differentially expressed in lymphoblastoid cell lines (LCLs) from individuals with ASD relative to controls.. Additional studies from our laboratory demonstrated that reduction in RORA expression is associated with increased methylation of the RORA promoter. Moreover, our studies showed that male and female hormones oppositely regulate the expression of RORA, with dihydrotestosterone (DHT) reducing RORA expression and estradiol increasing it. Since nuclear receptors and their associated coregulators can transcriptionally regulate many gene targets, dysregulated expression of nuclear receptors and coregulators can have widespread consequences on gene expression. However, the contribution of nuclear receptors and coregulators to altered regulation of gene expression in the autistic brain is still unknown. The goal of this study was therefore to evaluate the expression level of specific nuclear receptors and/or coregulator genes in the cerebellum and frontal cortex of individuals with autism and that of age-matched controls. Results showed that a number of nuclear receptor and coregulator genes are differentially expressed in post-mortem brain tissues from individuals with autism. Specifically, 13 genes are up-regulated in the cerebellum and frontal cortex of autistic subjects relative to age-matched controls. Nuclear receptor subfamily 4, group A member 1 (NR4A1) is the most up-regulated gene in autistic subjects, while androgen receptor (AR) is the most significantly up-regulated gene across both tissues. Interestingly, NR4A1 and AR are highly associated with some of the symptomatology and pathology of ASD. Therefore, NR4A1 and AR are proposed as novel, functionally relevant autism candidate genes.

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