Dataset Information

Transcriptional network analysis on brains reveals a potential regulatory role of PPP1R3F in autism spectrum disorders.

ABSTRACT:

Objective

This study aims at identifying master regulators of transcriptional networks in autism spectrum disorders (ASDs).

Results

With two sets of independent RNA-Seq data generated on cerebellum from patients with ASDs and control subjects (N?=?39 and 45 for set 1, N?=?24 and 38 for set 2, respectively), we carried out a network deconvolution of transcriptomic data, followed by virtual protein activity analysis. We identified PPP1R3F (Protein Phosphatase 1 Regulatory Subunit 3F) as a candidate master regulator affecting a large body of downstream genes that are associated with the disease phenotype. Pathway analysis on the identified targets of PPP1R3F in both datasets indicated alteration of endocytosis pathway. Despite a limited sample size, our study represents one of the first applications of network deconvolution approach to brain transcriptomic data to generate hypotheses that may be further validated by large-scale studies.

SUBMITTER: Doostparast Torshizi A

PROVIDER: S-EPMC6050725 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Transcriptional network analysis on brains reveals a potential regulatory role of PPP1R3F in autism spectrum disorders.

Doostparast Torshizi Abolfazl A Duan Jubao J Wang Kai K

BMC research notes 20180717 1

<h4>Objective</h4>This study aims at identifying master regulators of transcriptional networks in autism spectrum disorders (ASDs).<h4>Results</h4>With two sets of independent RNA-Seq data generated on cerebellum from patients with ASDs and control subjects (N = 39 and 45 for set 1, N = 24 and 38 for set 2, respectively), we carried out a network deconvolution of transcriptomic data, followed by virtual protein activity analysis. We identified PPP1R3F (Protein Phosphatase 1 Regulatory Subunit 3F ...[more]

PMID: 30016992

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Project description:Autism is currently considered a multigene disorder with epigenetic influences. To investigate the contribution of DNA methylation to autism spectrum disorders, we have recently completed large-scale methylation profiling by CpG island microarray analysis of lymphoblastoid cell lines (LCL) derived from monozygotic twins discordant for diagnosis of autism and their nonautistic siblings. Methylation profiling revealed many candidate genes differentially methylated between discordant MZ twins as well as between both twins and nonautistic siblings. Bioinformatics analysis of the differentially methylated genes demonstrated enrichment for high level functions including gene transcription, nervous system development, cell death/survival, and other biological processes implicated in autism. The methylation status of two of these candidate genes, BCL-2 and retinoic acid receptor (RAR)-related orphan receptor alpha (RORA), was further confirmed by bisulfite sequencing and methylation-specific PCR, respectively. Immunohistochemical analyses of tissue arrays containing slices of the cerebellum and frontal cortex of autistic and age- and sex-matched control subjects revealed decreased expression of RORA and BCL-2 proteins in the autistic brain. Our data thus confirm the role of epigenetic regulation of gene expression via differential DNA methylation in idiopathic autism, and furthermore link molecular changes in a peripheral cell model with brain pathobiology in autism. Global methylation profiling was performed on lymphoblastoid cell lines (LCLs) derived from three pairs of male monozygotic twins discordant for diagnosis of autism as determined by the Autism Diagnostic Interview-Revised (ADI-R). As controls, cell lines derived from non-autistic siblings of two pairs of twins were also included in the analyses, in addition to cell lines derived from a set of monozygotic twins unaffected by autism. For all paired analyses, a direct comparison was performed in which the methylation-enriched fractions from two individuals were pooled and hybridized onto the same microarray. In addition, indirect comparisons were performed by co-hybridizing the methylation-enriched (MIRA) fraction with the respective unenriched DNA fraction obtained from the same individual. For each paired analysis (between autistic MZ twins and/or between autistic co-twin and unaffected sibling), a total number of 4 replicates were performed, including direct and indirect comparisons.

Dataset Information

Transcriptional network analysis on brains reveals a potential regulatory role of PPP1R3F in autism spectrum disorders.

Objective

Results

Publications

Transcriptional network analysis on brains reveals a potential regulatory role of PPP1R3F in autism spectrum disorders.

Similar Datasets

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