Abstract
Long non-coding RNA (lncRNA) biology is a rapidly growing area of study. Thousands of lncRNAs are implicated as key players in cellular pathways and cancer biology. However, the structure–function relationships of these novel biomolecules are not well understood. Recent structural studies suggest that lncRNAs contain modular structural domains, which play a crucial role in their function. Here, we hypothesized that such structural domains exist in lncTCF7, a conserved lncRNA implicated in the development and progression of several cancers. To understand the structure–function relationship of lncTCF7, we characterized its secondary structure using chemical probing methods. Our model revealed structural domains and conserved regions in lncTCF7. One of the modular domains identified here coincides with a known protein-interacting domain. The model reported herein is, to our knowledge, the first structural model of lncTCF7 and thus will serve to direct future studies that will provide fundamental insights into the function of this lncRNA.
Highlights
Long non-coding RNAs are RNA molecules of at least 200 nucleotides in length that do not code for proteins [1]
As of 2019, there are 56,946 Long non-coding RNA (lncRNA) genes deposited in the LNCipedia database, many of which are dysregulated in several diseases, including cancer and viral infections [7,8,9]
In contrast to our expanding knowledge regarding the function of lncRNAs, the molecular details regarding their mechanisms of action are largely unknown [11,12]
Summary
Long non-coding RNAs (lncRNAs) are RNA molecules of at least 200 nucleotides in length that do not code for proteins [1]. For a more detailed list of lncRNA secondary structures, see Qian et al [12] Given this dearth of structural information on lncRNAs, and the increasing evidence of their biological importance, we have determined the secondary structure of the cancer-relevant lncTCF7 ( known as WSPAR; WNT signaling pathway activating non-coding RNA). The current model suggests that lncTCF7 recruits the SWI/SNF (mating-type switching/sucrose non-fermentable) complex to the promotor of the TCF7 gene, increasing transcription of the TCF7 and subsequently increasing signaling through the WNT pathway [33]. We validated our model using shotgun secondary structure (3S) analysis, and an orthogonal probing reagent, DMS (dimethyl sulfate). This combined analysis highlighted two potential regions of interest in lncTCF7, which show high confidence and low Shannon entropy. One of these regions (bases 468 to 683) has been previously shown to recruit the core components of SWI/SNF, suggesting a possible structure–function relationship
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