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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 categorization of miRNA target genes. KEGG pathways of the predicted gene targets of the microRNA that showed altered expression in ASD compared to control subjects in the PAC and in the STS. These pathways had more predicted regulated target genes in the pathway than would have been expected by chance (P < 0.05). Pathways are grouped according to categories in vertical text. Only miRNA differentially expressed in STS had target genes over-represented in immune related pathways and functions
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Fig4: Functional categorization of miRNA target genes. KEGG pathways of the predicted gene targets of the microRNA that showed altered expression in ASD compared to control subjects in the PAC and in the STS. These pathways had more predicted regulated target genes in the pathway than would have been expected by chance (P < 0.05). Pathways are grouped according to categories in vertical text. Only miRNA differentially expressed in STS had target genes over-represented in immune related pathways and functions

Mentions: Based on the microT-CDS algorithm (which includes coding and 3′ UTR sequences, threshold = 0.9), we found miRNA differentially expressed in ASD had 1214 predicted gene targets in PAC and 445 in STS (Additional file 1: Table S3). Over represented KEGG pathways that contained more gene targets than expected by chance (Fisher exact test, FDR corrected P < 0.05) are summarized in Fig. 4. KEGG pathways regulated by these miRNA showed little overlap between regions (Fig. 4). Indeed, only two pathways were shared between PAC and STS: “pathways in cancer”, which are cell cycle, cell differentiation, mitochondrion, and gene regulation focused, and the PI3K-Akt signaling pathway (Fig. 4). Another major finding is that immune pathways under control of the differentially expressed miRNA appear to be dysregulated only in STS whereas neuronal, cell cycle, signaling and cell processes were dysregulated in both PAC and STS in ASD compared to control subjects (Fig. 4).Fig. 4


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 categorization of miRNA target genes. KEGG pathways of the predicted gene targets of the microRNA that showed altered expression in ASD compared to control subjects in the PAC and in the STS. These pathways had more predicted regulated target genes in the pathway than would have been expected by chance (P < 0.05). Pathways are grouped according to categories in vertical text. Only miRNA differentially expressed in STS had target genes over-represented in immune related pathways and functions
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Functional categorization of miRNA target genes. KEGG pathways of the predicted gene targets of the microRNA that showed altered expression in ASD compared to control subjects in the PAC and in the STS. These pathways had more predicted regulated target genes in the pathway than would have been expected by chance (P < 0.05). Pathways are grouped according to categories in vertical text. Only miRNA differentially expressed in STS had target genes over-represented in immune related pathways and functions
Mentions: Based on the microT-CDS algorithm (which includes coding and 3′ UTR sequences, threshold = 0.9), we found miRNA differentially expressed in ASD had 1214 predicted gene targets in PAC and 445 in STS (Additional file 1: Table S3). Over represented KEGG pathways that contained more gene targets than expected by chance (Fisher exact test, FDR corrected P < 0.05) are summarized in Fig. 4. KEGG pathways regulated by these miRNA showed little overlap between regions (Fig. 4). Indeed, only two pathways were shared between PAC and STS: “pathways in cancer”, which are cell cycle, cell differentiation, mitochondrion, and gene regulation focused, and the PI3K-Akt signaling pathway (Fig. 4). Another major finding is that immune pathways under control of the differentially expressed miRNA appear to be dysregulated only in STS whereas neuronal, cell cycle, signaling and cell processes were dysregulated in both PAC and STS in ASD compared to control subjects (Fig. 4).Fig. 4

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