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Protein Abundance Control by Non-coding Antisense Transcription.

ABSTRACT: Stable unannotated transcripts (SUTs), some of which overlap protein-coding genes in antisense direction, are a class of non-coding RNAs. While case studies have reported important regulatory roles for several of such RNAs, their general impact on protein abundance regulation of the overlapping gene is not known. To test this, we employed seamless gene manipulation to repress antisense SUTs of 162 yeast genes by using a unidirectional transcriptional terminator and a GFP tag. We found that the mere presence of antisense SUTs was not sufficient to influence protein abundance, that observed effects of antisense SUTs correlated with sense transcript start site overlap, and that the effects were generally weak and led to reduced protein levels. Antisense regulated genes showed increased H3K4 di- and trimethylation and had slightly lower than expected noise levels. Our results suggest that the functionality of antisense RNAs has gene and condition-specific components.

SUBMITTER: Huber F

PROVIDER: S-EPMC4920891 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Protein Abundance Control by Non-coding Antisense Transcription.

Huber Florian F Bunina Daria D Gupta Ishaan I Khmelinskii Anton A Meurer Matthias M Theer Patrick P Steinmetz Lars M LM Knop Michael M

Cell reports 20160609 12

Stable unannotated transcripts (SUTs), some of which overlap protein-coding genes in antisense direction, are a class of non-coding RNAs. While case studies have reported important regulatory roles for several of such RNAs, their general impact on protein abundance regulation of the overlapping gene is not known. To test this, we employed seamless gene manipulation to repress antisense SUTs of 162 yeast genes by using a unidirectional transcriptional terminator and a GFP tag. We found that the m ...[more]

PMID: 27292640

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Project description:BackgroundAutism spectrum disorders (ASD) manifest with neurodevelopmental phenotypes including communicative, social and behavioral impairments that affect as many as 1 in 88 children. The majority of autism cases have no known genetic cause, suggesting complex genetics of the disorder, but a few genes of large effect have been identified.MethodsIn order to identify novel ASD genetic correlates, we investigated non-protein coding RNAs (ncRNAs) which are abundantly transcribed from the human genome, enriched in the brain, and have been implicated in neurodevelopmental disorders. Using an algorithm that we developed, we examined a publicly available transcriptomics database, AceView, to identify the natural antisense transcripts (NATs) that overlap with known autism-related genes. We validated the presence and differential expression of NATs in different brain regions of ASD and control brains using qRT-PCR. Additionally, we investigated the subcellular localization of these transcripts in a neuronal cell line using RNA-sequencing (RNA-seq).ResultsWe found noncoding antisense RNA transcripts at approximately 40% of loci previously implicated in ASD. We confirmed the expression of 10 antisense RNAs in different postmortem human brain tissues. The expression of five antisense transcripts was found to be region-specific, suggesting a role for these ncRNAs in the development and function of specific brain regions. Some antisense RNAs overlapping suspected ASD genes exhibited concordant expression relative to their sense protein-coding genes, while other sense-antisense pairs demonstrate a discordant relationship. Interestingly, the antisense RNA corresponding to the SYNGAP1 locus (SYNGAP1-AS) was found to be differentially expressed in brain regions of patients with ASD compared to control individuals. RNA-seq analysis of subcellular compartments from SH-SY5Y human neuroblastoma cells demonstrated that antisense RNAs to ASD candidate genes are predominantly expressed in the nucleoplasmic or chromatin compartments, implying their involvement in nuclear-associated processes.ConclusionsOur data suggests that NATs are abundantly expressed from ASD-related loci and provide evidence for their roles in target gene regulation, neurodevelopment and autism pathogenesis. This class of RNA should therefore be considered in functional studies aimed at understanding genetic risk factors for ASD.

Dataset Information

Protein Abundance Control by Non-coding Antisense Transcription.

Publications

Protein Abundance Control by Non-coding Antisense Transcription.

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