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A class of circadian long non-coding RNAs mark enhancers modulating long-range circadian gene regulation.

ABSTRACT: Circadian rhythm exerts its influence on animal physiology and behavior by regulating gene expression at various levels. Here we systematically explored circadian long non-coding RNAs (lncRNAs) in mouse liver and examined their circadian regulation. We found that a significant proportion of circadian lncRNAs are expressed at enhancer regions, mostly bound by two key circadian transcription factors, BMAL1 and REV-ERB?. These circadian lncRNAs showed similar circadian phases with their nearby genes. The extent of their nuclear localization is higher than protein coding genes but less than enhancer RNAs. The association between enhancer and circadian lncRNAs is also observed in tissues other than liver. Comparative analysis between mouse and rat circadian liver transcriptomes showed that circadian transcription at lncRNA loci tends to be conserved despite of low sequence conservation of lncRNAs. One such circadian lncRNA termed lnc-Crot led us to identify a super-enhancer region interacting with a cluster of genes involved in circadian regulation of metabolism through long-range interactions. Further experiments showed that lnc-Crot locus has enhancer function independent of lnc-Crot's transcription. Our results suggest that the enhancer-associated circadian lncRNAs mark the genomic loci modulating long-range circadian gene regulation and shed new lights on the evolutionary origin of lncRNAs.

SUBMITTER: Fan Z

PROVIDER: S-EPMC5449593 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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A class of circadian long non-coding RNAs mark enhancers modulating long-range circadian gene regulation.

Fan Zenghua Z Zhao Meng M Joshi Parth D PD Li Ping P Zhang Yan Y Guo Weimin W Xu Yichi Y Wang Haifang H Zhao Zhihu Z Yan Jun J

Nucleic acids research 20170601 10

Circadian rhythm exerts its influence on animal physiology and behavior by regulating gene expression at various levels. Here we systematically explored circadian long non-coding RNAs (lncRNAs) in mouse liver and examined their circadian regulation. We found that a significant proportion of circadian lncRNAs are expressed at enhancer regions, mostly bound by two key circadian transcription factors, BMAL1 and REV-ERBα. These circadian lncRNAs showed similar circadian phases with their nearby gene ...[more]

PMID: 28335007

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Project description:BACKGROUND:Long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of tissue-specific cellular functions and have been shown to regulate transcriptional and translational processes, acting as signals, decoys, guides, and scaffolds. It has been suggested that some lncRNAs act in cis to regulate the expression of neighboring protein-coding genes (PCGs) in a mechanism that fine-tunes gene expression. Gut microbiome is increasingly recognized as a regulator of development, inflammation, host metabolic processes, and xenobiotic metabolism. However, there is little known regarding whether the gut microbiome modulates lncRNA gene expression in various host metabolic organs. The goals of this study were to 1) characterize the tissue-specific expression of lncRNAs and 2) identify and annotate lncRNAs differentially regulated in the absence of gut microbiome. RESULTS:Total RNA was isolated from various tissues (liver, duodenum, jejunum, ileum, colon, brown adipose tissue, white adipose tissue, and skeletal muscle) from adult male conventional and germ-free mice (n =?3 per group). RNA-Seq was conducted and reads were mapped to the mouse reference genome (mm10) using HISAT. Transcript abundance and differential expression was determined with Cufflinks using the reference databases NONCODE 2016 for lncRNAs and UCSC mm10 for PCGs. Although the constitutive expression of lncRNAs was ubiquitous within the enterohepatic (liver and intestine) and the peripheral metabolic tissues (fat and muscle) in conventional mice, differential expression of lncRNAs by lack of gut microbiota was highly tissue specific. Interestingly, the majority of gut microbiota-regulated lncRNAs were in jejunum. Most lncRNAs were co-regulated with neighboring PCGs. STRING analysis showed that differentially expressed PCGs in proximity to lncRNAs form tissue-specific networks, suggesting that lncRNAs may interact with gut microbiota/microbial metabolites to regulate tissue-specific functions. CONCLUSIONS:This study is among the first to demonstrate that gut microbiota critically regulates the expression of lncRNAs not only locally in intestine but also remotely in other metabolic organs, suggesting that common transcriptional machinery may be shared to transcribe lncRNA-PCG pairs, and lncRNAs may interact with PCGs to regulate tissue-specific pathways.

Dataset Information

A class of circadian long non-coding RNAs mark enhancers modulating long-range circadian gene regulation.

Publications

A class of circadian long non-coding RNAs mark enhancers modulating long-range circadian gene regulation.

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