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Autism and increased paternal age related changes in global levels of gene expression regulation.

Alter MD, Kharkar R, Ramsey KE, Craig DW, Melmed RD, Grebe TA, Bay RC, Ober-Reynolds S, Kirwan J, Jones JJ, Turner JB, Hen R, Stephan DA - PLoS ONE (2011)

Bottom Line: This premise can be tested by evaluating for changes in the overall distribution of gene expression levels.Variance in the distribution of gene expression levels from each microarray was compared between groups of children.Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. markalter1968@gmail.com

ABSTRACT
A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in variance might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on RNA from peripheral blood lymphocytes (PBL) of children with autism (n = 82) and controls (n = 64). Variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance. A decrease in the variance in the distribution of gene expression levels in PBL was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Global regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other neurodevelopmental disorders.

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Transcription inhibitors lead to decreased variance in gene expression.Gene expression data from a publically available dataset show that treatment of a lung cancer cell line with actinomycin D and a high dose of sapphyrin results in decreased variance in gene expression compared to treatment with mannitol or a low dose of sapphyrin. Error bars represent standard error.
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pone-0016715-g005: Transcription inhibitors lead to decreased variance in gene expression.Gene expression data from a publically available dataset show that treatment of a lung cancer cell line with actinomycin D and a high dose of sapphyrin results in decreased variance in gene expression compared to treatment with mannitol or a low dose of sapphyrin. Error bars represent standard error.

Mentions: Cross-validation of pathway analysis indicated that these findings were highly robust. Significant gene lists from subgroups (Autism1 vs. Young father1, Autism2 vs. Young father2, Old father1 vs. Young father1, and Old father2 vs. Young father2) indicated that in all cases, significantly down-regulated genes in children with autism or children of older fathers were enriched for genes involved in transcription (Table S1). It was also noted in these analyses that, in all cases, sets of down-regulated genes were also enriched for zinc finger C2H2 proteins and for genes involved in zinc pathways. Zinc has a well-documented role in neurodevelopment[36], [37], [38] and also plays any important role in the stabilization of many proteins involved in transcription[38], suggesting that zinc-mediated effects on transcription may be particularly important in contributing to global effects on gene expression.


Autism and increased paternal age related changes in global levels of gene expression regulation.

Alter MD, Kharkar R, Ramsey KE, Craig DW, Melmed RD, Grebe TA, Bay RC, Ober-Reynolds S, Kirwan J, Jones JJ, Turner JB, Hen R, Stephan DA - PLoS ONE (2011)

Transcription inhibitors lead to decreased variance in gene expression.Gene expression data from a publically available dataset show that treatment of a lung cancer cell line with actinomycin D and a high dose of sapphyrin results in decreased variance in gene expression compared to treatment with mannitol or a low dose of sapphyrin. Error bars represent standard error.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040743&req=5

pone-0016715-g005: Transcription inhibitors lead to decreased variance in gene expression.Gene expression data from a publically available dataset show that treatment of a lung cancer cell line with actinomycin D and a high dose of sapphyrin results in decreased variance in gene expression compared to treatment with mannitol or a low dose of sapphyrin. Error bars represent standard error.
Mentions: Cross-validation of pathway analysis indicated that these findings were highly robust. Significant gene lists from subgroups (Autism1 vs. Young father1, Autism2 vs. Young father2, Old father1 vs. Young father1, and Old father2 vs. Young father2) indicated that in all cases, significantly down-regulated genes in children with autism or children of older fathers were enriched for genes involved in transcription (Table S1). It was also noted in these analyses that, in all cases, sets of down-regulated genes were also enriched for zinc finger C2H2 proteins and for genes involved in zinc pathways. Zinc has a well-documented role in neurodevelopment[36], [37], [38] and also plays any important role in the stabilization of many proteins involved in transcription[38], suggesting that zinc-mediated effects on transcription may be particularly important in contributing to global effects on gene expression.

Bottom Line: This premise can be tested by evaluating for changes in the overall distribution of gene expression levels.Variance in the distribution of gene expression levels from each microarray was compared between groups of children.Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. markalter1968@gmail.com

ABSTRACT
A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in variance might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on RNA from peripheral blood lymphocytes (PBL) of children with autism (n = 82) and controls (n = 64). Variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance. A decrease in the variance in the distribution of gene expression levels in PBL was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Global regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other neurodevelopmental disorders.

Show MeSH
Related in: MedlinePlus