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Xiaohua Shen’s group reported a general theme of 

RNA-mediated transcription regulation 



  Published online in Cell Stem Cell on March 17, 2016, the research team led by Dr. Xiaohua Shen from Center for Life Sciences reported a prevalent phenomenon of RNA-mediated transcription regulation on nearby genes. 


Web link for this paper : http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(16)00062-X


  Although it is believed that proteins are the major executors of cellular and organism functions, metazoans have a relatively common set of protein-coding genes despite different genome sizes and developmental complexity. In fact, only 1.5% of the human genome encodes proteins, while 80% of the genome is transcribed and produces thousands of long noncoding RNA (lncRNA) transcripts. To date, our knowledge is still limited to a handful of them. The functionality of lncRNAs is largely unknown. Identifying functional lncRNAs and then inferring biological pathways in which they act in are important challenges into understanding the genome complexity and RNA-mediated gene regulation.


  While main efforts in the field have been focused on individual genes, Xiaohua’s group (Figure 1) sought to classify lncRNAs and infer their functions. Yuyang Lu, a graduate student in her group, categorized lncRNAs according to their proximity and orientation with respect to protein-coding loci and uncovered a non-random distribution in the genome. Among lncRNA biotypes, divergent lncRNAs represent an interesting class (Figure 2). They are transcribed oppositely from nearby protein-coding genes, account for a significant portion (~20%) of lncRNAs in mammalian genomes, show strong correlation and coexpression with genes of essential regulatory functions in development, and have deeper evolutionary origin compared to intergenic lncRNAs. 




  Genomic juxtaposition of divergent lncRNA and protein-coding genes suggests a potential regulatory link. To test this hypothesis, Sai Luo, a graduate student and the first author in the paper, knocked down a number of lncRNAs and protein-coding genes that were randomly picked. Remarkably, depletion of 75% divergent lncRNAs led to downregulation of nearby genes, while protein-coding transcripts had a neglectable effect on nearby transcription. Some lncRNA knockdown elicited global expression changes in developmental programs known to involve nearby transcription factors. In-depth characterization of the divergent Evx1as/EVX1 locus revealed a direct role for the Evx1as lncRNA transcripts to promote EVX1 transcription in cis, and to regulate stem cell differentiation. At a single-cell level, early broad expression of Evx1as is followed by a rapid, high-level transcription of EVX1, supporting the idea that Evx1as plays an upstream role to facilitate EVX1 transcription. Mechanistically, Evx1as RNA binds to regulatory sites on chromatin, promotes an active chromatin state and interacts with Mediator (Figure 2). 




  Thus, they concluded that divergent lncRNAs, or at least a subset of them, can positively regulate the transcription of nearby genes and participate in biological processes similar to those controlled by the nearby protein-coding genes (Figure 2). Cis-regulation of nearby transcription by divergent lncRNAs may represent a general theme in mammalian gene regulation. From this point of view, the functionality of thousands of uncharacterized lncRNA genes can be rapidly predicted on the basis of the knowledge of their neighboring genes. This functional inference may help to generate meaningful hypothesis and design experiments to investigate lncRNA transcripts whose functions are largely unknown.


  Previously, Xiaohua’s group reported that a lncRNA’s transcripts and its genomic locus can have opposing functions in regulating the same target genes (Yin et al., 2015. Cell Stem Cell). They proposed that lncRNA transcripts may serve as a flexible regulator to convey subtle regulatory information carried in the genome DNA. Together, recent works in Xiaohua’s group support the view that RNA represents a hidden layer of regulatory information in complex organisms. Considering the prevalence of lncRNA genes in mammalian genomes, lncRNA-mediated transcription fine-tuning may have significant impacts on animal development and fitness. 


  This work was supported by the Center for Life Sciences (CLS) at Tsinghua University, National Basic Research Program and National Natural Science Foundation of China.


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