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Identification of amygdala-expressed genes associated with autism spectrum disorder.

ABSTRACT: BACKGROUND:Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be associated with ASD core behaviors they must be: (1) expressed in brain regions relevant to ASD social behaviors and (2) expressed during the ASD susceptible window of brain development. METHODS:Focusing on the amygdala, a brain region whose dysfunction has been highly implicated in the social component of ASD, we mined publicly available gene expression databases to identify ASD-susceptibility genes expressed during human and mouse amygdala development. We found that a large cohort of known ASD susceptibility genes is expressed in the developing human and mouse amygdala. We further performed analysis of single-nucleus RNA-seq (snRNA-seq) data from microdissected amygdala tissue from five ASD and five control human postmortem brains ranging in age from 4 to 20?years to elucidate cell type specificity of amygdala-expressed genes and their dysregulation in ASD. RESULTS:Our analyses revealed that of the high-ranking ASD susceptibility genes, 80 are expressed in both human and mouse amygdala during fetal to early postnatal stages of development. Our human snRNA-seq analyses revealed cohorts of genes with altered expression in the ASD amygdala postnatally, especially within excitatory neurons, with dysregulated expression of seven genes predicted from our datamining pipeline. LIMITATIONS:We were limited by the ages for which we were able to obtain human tissue; therefore, the results from our datamining pipeline approach will require validation, to the extent possible, in human tissue from earlier developmental stages. CONCLUSIONS:Our pipeline narrows down the number of amygdala-expressed genes possibly involved in the social pathophysiology of ASD. Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala.

SUBMITTER: Herrero MJ

PROVIDER: S-EPMC7251751 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Identification of amygdala-expressed genes associated with autism spectrum disorder.

Herrero Maria Jesus MJ Velmeshev Dmitry D Hernandez-Pineda David D Sethi Saarthak S Sorrells Shawn S Banerjee Payal P Sullivan Catherine C Gupta Abha R AR Kriegstein Arnold R AR Corbin Joshua G JG

Molecular autism 20200527 1

<h4>Background</h4>Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be ass ...[more]

PMID: 32460837

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Project description:Background: We have recently identified the nuclear hormone receptor RORA (retinoic acid-related orphan receptor-alpha) as a novel candidate gene for autism spectrum disorder (ASD). Our independent cohort studies have consistently demonstrated the reduction of RORA transcript and/or protein levels in blood-derived lymphoblasts as well as the postmortem prefrontal cortex and cerebellum of individuals with ASD. Moreover, we have also shown that RORA has the potential to be under negative and positive regulation by androgen and estrogen, respectively, suggesting the possibility that RORA may contribute to the male bias of ASD. However, little is known about transcriptional targets of this nuclear receptor, particularly in humans. Methods: Here we comprehensively identify transcriptional targets of RORA in human neuronal cells using chromatin immunoprecipitation (ChIP), followed by whole-genome promoter array (chip) analysis. Selected potential targets of RORA were then further validated by an independent chromatin immunoprecipitation, followed by qPCR analysis. To further demonstrate that reduced RORA expression results in aberrant transcription of RORA targets, we determined the expression levels of selected transcriptional targets in RORA-deficient human neuronal cells, as well as in postmortem brain tissues from individuals with ASD who exhibit reduced RORA expression. Results: The ChIP-on-chip analysis reveals that RORA1, a major isoform of RORA protein in human brain, can be recruited to as many as 1,338 genomic locations corresponding to promoter regions of 1,274 genes across the human genome. Among the genes potentially directly regulated by RORA1 are genes known to have biological functions negatively impacted in individuals with ASD, including neuronal adhesion and survival, synaptogenesis, and development of the cortex and the cerebellum. Independent ChIP-qPCR analyses confirm binding of RORA1 to promoter regions of several ASD-associated genes, including A2BP1, CYP19A1, HSD17B10, ITPR1, NLGN1, and NTRK2, whose expression levels are also decreased in RORA1-repressed human neuronal cells and in prefrontal cortex tissues from individuals with ASD. Conclusion: Findings from this study indicate that RORA transcriptionally regulates A2BP1, CYP19A1, HSD17B10, ITPR1, NLGN1, and NTRK2, and strongly suggest that reduction of this sex hormone-sensitive nuclear receptor in the brain causes dysregulated expression of these genes which, in turn, may contribute to the underlying pathobiology of ASD. Nuclear lysates from the human neuroblastoma cell line SH-SY5Y were chromatin-immunoprecipitated with goat anti-RORA1 antibody vs. normal goat IgG antibody

Dataset Information

Identification of amygdala-expressed genes associated with autism spectrum disorder.

Publications

Identification of amygdala-expressed genes associated with autism spectrum disorder.

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