Aberrant Expression of Long Noncoding RNAs in Autistic Brain

Abstract

The autism spectrum disorders (ASD) have a significant hereditary component, but the implicated genetic loci are heterogeneous and complex. Consequently, there is a gap in understanding how diverse genomic aberrations all result in one clinical ASD phenotype. Gene expression studies from autism brain tissue have demonstrated that aberrantly expressed protein-coding genes may converge onto common molecular pathways, potentially reconciling the strong heritability and shared clinical phenotypes with the genomic heterogeneity of the disorder. However, the regulation of gene expression is extremely complex and governed by many mechanisms, including noncoding RNAs. Yet no study in ASD brain tissue has assessed for changes in regulatory long noncoding RNAs (lncRNAs), which represent a large proportion of the human transcriptome, and actively modulate mRNA expression. To assess if aberrant expression of lncRNAs may play a role in the molecular pathogenesis of ASD, we profiled over 33,000 annotated lncRNAs and 30,000 mRNA transcripts from postmortem brain tissue of autistic and control prefrontal cortex and cerebellum by microarray. We detected over 200 differentially expressed lncRNAs in ASD, which were enriched for genomic regions containing genes related to neurodevelopment and psychiatric disease. Additionally, comparison of differences in expression of mRNAs between prefrontal cortex and cerebellum within individual donors showed ASD brains had more transcriptional homogeneity. Moreover, this was also true of the lncRNA transcriptome. Our results suggest that further investigation of lncRNA expression in autistic brain may further elucidate the molecular pathogenesis of this disorder.Electronic supplementary materialThe online version of this article (doi:10.1007/s12031-012-9880-8) contains supplementary material, which is available to authorized users.

Differential expression of long non-coding RNAs in bleomycin-induced lung fibrosis

“…Dharap et al found 62 stroke-responsive lncRNAs showing 90% sequence homology with exons of protein-coding genes in their study on lncRNA expression profiles in focal ischemia (35). Similarly, Ziats et al reported that most differentially expressed lncRNAs in autism spectrum disorders (ASD) were from intergenic regions (~60%), from antisense to proteincoding loci (~15%), or within introns of protein-coding genes (~10%), with the others representing overlapping transcripts from exons or introns in both sense and antisense directions (36). Another complicating factor is the presence of bifunctional RNAs, which are transcripts that function as non-coding transcripts under certain conditions and are translated into functional proteins in other situations (37,38).…”

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

“…In a lncRNAs transcriptome study of post-mortem brain tissue of ASD patients [63], 222 differentially expressed lncRNAs between ASD and controls were identified, with an enrichment of genes associated with neuronal migration. It should be cautioned that the sample size was small with only 2 patient samples with 2 controls in this study.…”

Long Non-coding RNAs: Novel Targets for Nervous System Disease Diagnosis and Therapy

“…Profiling lncRNAs in the nucleus accumbens of cocaine-conditioned mice, an animal model that exhibits aberrant plasticity, revealed hundreds of differentially expressed lncRNAs, including those associated with plasticity-related genes [44]. lncRNAs are similarly deregulated in relevant human neuropathological specimens from patients with alcohol and heroin addiction, as well as other disorders characterized by abnormal plasticity, such as autism and intractable epilepsy [45][46][47][48]. Many of these lncRNAs are linked with genes that have key roles in longterm potentiation, synaptic activity and memory, such as brainderived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated protein.…”

“…These include, as examples, lncRNA signatures in neuropathological specimens from patients with AD [86], addiction to alcohol [46], addiction to heroin [45], autism [47], gliomas [87,88], Huntington's disease [89], and pituitary adenomas [90]. Importantly, these abnormal expression patterns are not only found in brain but they can also be present in more accessible fluids and tissues.…”