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Atypical miRNA expression in temporal cortex associated with dysregulation of immune, cell cycle, and other pathways in autism spectrum disorders.

Ander BP, Barger N, Stamova B, Sharp FR, Schumann CM - Mol Autism (2015)

Bottom Line: We assessed whether a brain region associated with core social impairments in ASD, the superior temporal sulcus (STS), would evidence greater transcriptional dysregulation of sncRNA than adjacent, yet functionally distinct, primary auditory cortex (PAC).Immune pathways were only disrupted in STS. snoRNA and pre-miRNA were also differentially expressed in ASD brain.Disruption of miRNA in immune pathways, frequently implicated in ASD, was unique to STS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, MIND Institute, University of California at Davis Medical Center, 2805 50th Street, Sacramento, CA 95817 USA.

ABSTRACT

Background: Autism spectrum disorders (ASDs) likely involve dysregulation of multiple genes related to brain function and development. Abnormalities in individual regulatory small non-coding RNA (sncRNA), including microRNA (miRNA), could have profound effects upon multiple functional pathways. We assessed whether a brain region associated with core social impairments in ASD, the superior temporal sulcus (STS), would evidence greater transcriptional dysregulation of sncRNA than adjacent, yet functionally distinct, primary auditory cortex (PAC).

Methods: We measured sncRNA expression levels in 34 samples of postmortem brain from STS and PAC to find differentially expressed sncRNA in ASD compared with control cases. For differentially expressed miRNA, we further analyzed their predicted mRNA targets and carried out functional over-representation analysis of KEGG pathways to examine their functional significance and to compare our findings to reported alterations in ASD gene expression.

Results: Two mature miRNAs (miR-4753-5p and miR-1) were differentially expressed in ASD relative to control in STS and four (miR-664-3p, miR-4709-3p, miR-4742-3p, and miR-297) in PAC. In both regions, miRNA were functionally related to various nervous system, cell cycle, and canonical signaling pathways, including PI3K-Akt signaling, previously implicated in ASD. Immune pathways were only disrupted in STS. snoRNA and pre-miRNA were also differentially expressed in ASD brain.

Conclusions: Alterations in sncRNA may underlie dysregulation of molecular pathways implicated in autism. sncRNA transcriptional abnormalities in ASD were apparent in STS and in PAC, a brain region not directly associated with core behavioral impairments. Disruption of miRNA in immune pathways, frequently implicated in ASD, was unique to STS.

No MeSH data available.


Related in: MedlinePlus

Functional similarities to other studies looking at ASD-related genes. Overlap of KEGG pathways identified through analysis of mRNA targets of brain miRNA in ASD and control brain from the STS and PAC combined analysis with previously published and compiled gene lists associated with ASD in (a) studies with transcriptional measurements of ASD brain (Garbett et al. [33] and Voineagu et al. [4]) and (b) sets of genes associated with ASD (Pinto et al. [34] and Abrahams et al. (SFARI) [35]). Numbers indicate KEGG pathways significantly over-represented by mRNA in the respective data set. The 44 KEGG pathways overlapping between this study, SFARI, and Pinto et al. appear in Additional file 1: Table S4
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Fig5: Functional similarities to other studies looking at ASD-related genes. Overlap of KEGG pathways identified through analysis of mRNA targets of brain miRNA in ASD and control brain from the STS and PAC combined analysis with previously published and compiled gene lists associated with ASD in (a) studies with transcriptional measurements of ASD brain (Garbett et al. [33] and Voineagu et al. [4]) and (b) sets of genes associated with ASD (Pinto et al. [34] and Abrahams et al. (SFARI) [35]). Numbers indicate KEGG pathways significantly over-represented by mRNA in the respective data set. The 44 KEGG pathways overlapping between this study, SFARI, and Pinto et al. appear in Additional file 1: Table S4

Mentions: In order to contrast the biological and functional significance of our study with studies previously reporting gene or gene expression lists associated with autism spectrum disorder, we performed functional over-representation analysis on KEGG pathways using reported data from two prior analyses of temporal cortex in ASD, Voineagu et al. (135 probes) [4] and Garbett et al. (152 probe sets) [33], and two datasets broadly focusing on ASD-associated genes, Pinto et al. (139 genes) [34] and the SFARI database of positively associated ASD genes (573 genes) [35]. Datasets were input into the online WebGestalt tool [36] to derive the KEGG pathway data for Fig. 5. Predicted gene targets from our study were taken from microT-CDS after combining all brain samples (STS and PAC) and then deriving miRNA that were different between ASD and CTRL groups (P < 0.005, fold change > /1.2/). Combining temporal regions allowed for a more appropriate comparison to the previous studies that did not target specific functional territories. Euler diagrams of area proportional overlap were generated using eulerAPE [37].


Atypical miRNA expression in temporal cortex associated with dysregulation of immune, cell cycle, and other pathways in autism spectrum disorders.

Ander BP, Barger N, Stamova B, Sharp FR, Schumann CM - Mol Autism (2015)

Functional similarities to other studies looking at ASD-related genes. Overlap of KEGG pathways identified through analysis of mRNA targets of brain miRNA in ASD and control brain from the STS and PAC combined analysis with previously published and compiled gene lists associated with ASD in (a) studies with transcriptional measurements of ASD brain (Garbett et al. [33] and Voineagu et al. [4]) and (b) sets of genes associated with ASD (Pinto et al. [34] and Abrahams et al. (SFARI) [35]). Numbers indicate KEGG pathways significantly over-represented by mRNA in the respective data set. The 44 KEGG pathways overlapping between this study, SFARI, and Pinto et al. appear in Additional file 1: Table S4
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4491207&req=5

Fig5: Functional similarities to other studies looking at ASD-related genes. Overlap of KEGG pathways identified through analysis of mRNA targets of brain miRNA in ASD and control brain from the STS and PAC combined analysis with previously published and compiled gene lists associated with ASD in (a) studies with transcriptional measurements of ASD brain (Garbett et al. [33] and Voineagu et al. [4]) and (b) sets of genes associated with ASD (Pinto et al. [34] and Abrahams et al. (SFARI) [35]). Numbers indicate KEGG pathways significantly over-represented by mRNA in the respective data set. The 44 KEGG pathways overlapping between this study, SFARI, and Pinto et al. appear in Additional file 1: Table S4
Mentions: In order to contrast the biological and functional significance of our study with studies previously reporting gene or gene expression lists associated with autism spectrum disorder, we performed functional over-representation analysis on KEGG pathways using reported data from two prior analyses of temporal cortex in ASD, Voineagu et al. (135 probes) [4] and Garbett et al. (152 probe sets) [33], and two datasets broadly focusing on ASD-associated genes, Pinto et al. (139 genes) [34] and the SFARI database of positively associated ASD genes (573 genes) [35]. Datasets were input into the online WebGestalt tool [36] to derive the KEGG pathway data for Fig. 5. Predicted gene targets from our study were taken from microT-CDS after combining all brain samples (STS and PAC) and then deriving miRNA that were different between ASD and CTRL groups (P < 0.005, fold change > /1.2/). Combining temporal regions allowed for a more appropriate comparison to the previous studies that did not target specific functional territories. Euler diagrams of area proportional overlap were generated using eulerAPE [37].

Bottom Line: We assessed whether a brain region associated with core social impairments in ASD, the superior temporal sulcus (STS), would evidence greater transcriptional dysregulation of sncRNA than adjacent, yet functionally distinct, primary auditory cortex (PAC).Immune pathways were only disrupted in STS. snoRNA and pre-miRNA were also differentially expressed in ASD brain.Disruption of miRNA in immune pathways, frequently implicated in ASD, was unique to STS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, MIND Institute, University of California at Davis Medical Center, 2805 50th Street, Sacramento, CA 95817 USA.

ABSTRACT

Background: Autism spectrum disorders (ASDs) likely involve dysregulation of multiple genes related to brain function and development. Abnormalities in individual regulatory small non-coding RNA (sncRNA), including microRNA (miRNA), could have profound effects upon multiple functional pathways. We assessed whether a brain region associated with core social impairments in ASD, the superior temporal sulcus (STS), would evidence greater transcriptional dysregulation of sncRNA than adjacent, yet functionally distinct, primary auditory cortex (PAC).

Methods: We measured sncRNA expression levels in 34 samples of postmortem brain from STS and PAC to find differentially expressed sncRNA in ASD compared with control cases. For differentially expressed miRNA, we further analyzed their predicted mRNA targets and carried out functional over-representation analysis of KEGG pathways to examine their functional significance and to compare our findings to reported alterations in ASD gene expression.

Results: Two mature miRNAs (miR-4753-5p and miR-1) were differentially expressed in ASD relative to control in STS and four (miR-664-3p, miR-4709-3p, miR-4742-3p, and miR-297) in PAC. In both regions, miRNA were functionally related to various nervous system, cell cycle, and canonical signaling pathways, including PI3K-Akt signaling, previously implicated in ASD. Immune pathways were only disrupted in STS. snoRNA and pre-miRNA were also differentially expressed in ASD brain.

Conclusions: Alterations in sncRNA may underlie dysregulation of molecular pathways implicated in autism. sncRNA transcriptional abnormalities in ASD were apparent in STS and in PAC, a brain region not directly associated with core behavioral impairments. Disruption of miRNA in immune pathways, frequently implicated in ASD, was unique to STS.

No MeSH data available.


Related in: MedlinePlus