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Cell minireview：
Long Noncoding RNAs Usher In a New Era in the Biology of Enhancerssummary:
Enhancer-associated long noncoding RNAs act over long distances and across chromosomes to activate transcription at distal promoters. Here, we address the latest advances made toward understanding the role of long noncoding RNA expression and the involvement of these RNAs in enhancer function through association with protein factors and modulation of chromatin structure.
Long Noncoding RNAs in Enhancer Looping and FunctionLong noncoding RNAs are proposed to function in the establishment or maintenance of enhancer promoter looping and activation of gene expression. In the absence of looping interactions (upper-left), the enhancer is inactive and transcription is minimal. One model for activation (counterclockwise) features engagement of enhancer-binding factors, transcription factors, and bridging factors such as the Mediator, Cohesin, and WDR5 complexes (lower-left), which leads to gene looping between enhancer and promoter sequences followed by induction of long noncoding RNA expression and transcriptional activation of the target gene (lower-right). A second model proposes that long noncoding RNA transcription precedes target gene activation and looping (clockwise), whereby binding of enhancer-binding factors and transcription of long noncoding RNAs are the first steps in the activation process (upper-right). Subsequently, a loop to the promoter is established through interactions with the transcription factors and bridging factors (lower-right), leading to activation of the neighboring gene.
The discovery of long noncoding RNAs with activating function and their intimate association with distal regulatory elements (enhancers) has profound implications for our understanding of gene regulation during differentiation, development, and disease progression. We have spent the last 20 years analyzing gene expression programs in healthy tissues and in disease states by profiling expression changes in protein-coding genes.The realization that tissue- and temporal-specific regulation of gene expression is governed by long noncoding RNAs expressed at enhancers provides us with an opportunity to analyze additional key regulatory molecules that may provide a greater insight into locus-specific gene regulation during disease development and progression. （这句话快看哭了！）Moreover, although recent experiments have shed some light on the mechanisms by which this class of long noncoding RNAs functions, we are still in the early stages of fully understanding the long noncoding RNA code(s) required for activating function. （任重而道远！）It will be highly informative to understand the long noncoding RNA sequence determinants or structural requirements (secondary or tertiary) that govern enhancer function. It is also of prime importance to determine the allele specificity of the RNAs’ activating function. Though multiple studies have pointed to cis-mediated function of some activating RNAs, whether activation is restricted to a single allele or can extend to both alleles has not been addressed and is a critical question that may reveal a broad and critical function for activating long noncoding RNAs in dosage compensation.
Given that RNA is an evolutionary predecessor of proteins, long noncoding RNA-mediated regulation of transcription may represent an ancient mechanism by which gene expression was regulated long before the appearance of proteins. As we continue to accumulate insights into these regulatory RNAs, it only becomes more apparent that there are new and unanticipated layers of regulation for tissue- and temporal-specific gene expression waiting to be discovered.
https://m.sciencenet.cn/blog-982855-725717.html
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