Epigenetic regulation of human cis-natural antisense transcripts

School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Nucleic Acids Research (Impact Factor: 9.11). 02/2012; 40(4):1438-45. DOI: 10.1093/nar/gkr1010
Source: PubMed


Mammalian genomes encode numerous cis-natural antisense transcripts (cis-NATs). The extent to which these cis-NATs are actively regulated and ultimately functionally relevant, as opposed to transcriptional noise, remains a matter of
debate. To address this issue, we analyzed the chromatin environment and RNA Pol II binding properties of human cis-NAT promoters genome-wide. Cap analysis of gene expression data were used to identify thousands of cis-NAT promoters, and profiles of nine histone modifications and RNA Pol II binding for these promoters in ENCODE cell types
were analyzed using chromatin immunoprecipitation followed by sequencing (ChIP-seq) data. Active cis-NAT promoters are enriched with activating histone modifications and occupied by RNA Pol II, whereas weak cis-NAT promoters are depleted for both activating modifications and RNA Pol II. The enrichment levels of activating histone
modifications and RNA Pol II binding show peaks centered around cis-NAT transcriptional start sites, and the levels of activating histone modifications at cis-NAT promoters are positively correlated with cis-NAT expression levels. Cis-NAT promoters also show highly tissue-specific patterns of expression. These results suggest that human cis-NATs are actively transcribed by the RNA Pol II and that their expression is epigenetically regulated, prerequisites for
a functional potential for many of these non-coding RNAs.

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    • "We consider three possible mechanisms: (a) regulation of transcription of NAT-SRN or (b) degradation of NAT-SRN in specific compartments, or (c) changes in axonal transport of NAT-SRN to neurites. It has been shown that expression of NATs could be regulated by epigenetic mechanisms (Conley and Jordan, 2012). We find that exposure to forskolin cause a rapid increase in sense transcripts in cell body and increase in NAT-SRN in neurites. "
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    ABSTRACT: Despite the advances in our understanding of transcriptome, regulation and function of its non-coding components continue to be poorly understood. Here we searched for natural antisense transcript for sensorin (NAT-SRN), a neuropeptide expressed in the presynaptic sensory neurons of gill-withdrawal reflex of the marine snail Aplysia californica. Sensorin (SRN) has a key role in learning and long-term memory storage in Aplysia. We have now identified NAT-SRN in the central nervous system (CNS) and have confirmed its expression by northern blotting and fluorescent RNA in situ hybridization. Quantitative analysis of NAT-SRN in micro-dissected cell bodies and processes of sensory neurons suggest that NAT-SRN is present in the distal neuronal processes along with sense transcripts. Importantly, aging is associated with reduction in levels of NAT-SRN in sensory neuron processes. Furthermore, we find that forskolin, an activator of CREB signaling, differentially alters the distribution of SRN and NAT-SRN. These studies reveal novel insights into physiological regulation of natural antisense RNAs.
    Frontiers in Genetics 04/2014; 5:84. DOI:10.3389/fgene.2014.00084
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    • "The expression of human cis-NATs transcribed by RNA Pol II is epigenetically regulated (Conley and Jordan, 2012), and aberrant production of these transcripts has been linked with human disease. Prader–Willi and Angelman syndromes, due to UBE3A expression, are affected due to the presence of a 20-kb NAT, which shares complementary sequences of UBE3A (Runte et al, 2001). "
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    ABSTRACT: The world of non-coding RNAs has only recently started being discovered. For the past 40 years, coding genes, mRNA, and proteins have been the center of cellular and molecular biology, and pathologic alterations were attributed to either the aberration of gene sequence or altered promoter activity. It was only after the completion of the human genome sequence that the scientific community started seriously wondering why only a very small portion of the genome corresponded to protein-coding genes. New technologies such as the whole-genome and whole-transcriptome sequencing demonstrated that at least 90% of the genome is actively transcribed. The identification and cataloguing of multiple kinds of non-coding RNA (ncRNA) have exponentially increased, and it is now widely accepted that ncRNAs play major biological roles in cellular physiology, development, metabolism, and are also implicated in a variety of diseases. The aim of this review is to describe the two major classes (long and short forms) of non-coding RNAs and describe their subclasses in terms of function and their relevance and potential in oral diseases.
    Oral Diseases 05/2013; 20(3). DOI:10.1111/odi.12142 · 2.43 Impact Factor
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    • "Chromatin structure had been shown to affect the accessibility of RNA polymerase II and other transcription factors to the site of transcription by means of methylation and acetylation [42,43]; thereby, playing an important factor in regulating gene expression. However, the role of chromatin structure in antisense transcript regulation had only been recently reported by [10] using chromatin immuno-precipitation and demonstrated positive correlation between cis-NAT promoter activity, the presence of RNA polymerase II histones modification and the resulting antisense RNA-seq read density, suggesting that chromatin structure also may be involved in cis-NAT transcription. "
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    ABSTRACT: Background Recent studies had found thousands of natural antisense transcripts originating from the same genomic loci of protein coding genes but from the opposite strand. It is unclear whether the majority of antisense transcripts are functional or merely transcriptional noise. Results Using the Affymetrix Exon array with a modified cDNA synthesis protocol that enables genome-wide detection of antisense transcription, we conducted large-scale expression analysis of antisense transcripts in nine corresponding tissues from human, mouse and rat. We detected thousands of antisense transcripts, some of which show tissue-specific expression that could be subjected to further study for their potential function in the corresponding tissues/organs. The expression patterns of many antisense transcripts are conserved across species, suggesting selective pressure on these transcripts. When compared to protein-coding genes, antisense transcripts show a lesser degree of expression conservation. We also found a positive correlation between the sense and antisense expression across tissues. Conclusion Our results suggest that natural antisense transcripts are subjected to selective pressure but to a lesser degree compared to sense transcripts in mammals.
    BMC Genomics 04/2013; 14(1):243. DOI:10.1186/1471-2164-14-243 · 3.99 Impact Factor
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