Abstract
Long noncoding RNAs (lncRNAs) influence cellular function through binding events that often depend on the lncRNA secondary structure. One such lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), is upregulated in many cancer types and has a myriad of protein- and miRNA-binding sites. Recently, a secondary structural model of MALAT1 in noncancerous cells was proposed to form 194 hairpins and 13 pseudoknots. That study postulated that, in cancer cells, the MALAT1 structure likely varies, thereby influencing cancer progression. This work analyzes how that structural model is expected to change in K562 cells, which originated from a patient with chronic myeloid leukemia (CML), and in HeLa cells, which originated from a patient with cervical cancer. Dimethyl sulfate-sequencing (DMS-Seq) data from K562 cells and psoralen analysis of RNA interactions and structure (PARIS) data from HeLa cells were compared to the working structural model of MALAT1 in noncancerous cells to identify sites that likely undergo structural alterations. MALAT1 in K562 cells is predicted to become more unstructured, with almost 60% of examined hairpins in noncancerous cells losing at least half of their base pairings. Conversely, MALAT1 in HeLa cells is predicted to largely maintain its structure, undergoing 18 novel structural rearrangements. Moreover, 50 validated miRNA-binding sites are affected by putative secondary structural changes in both cancer types, such as miR-217 in K562 cells and miR-20a in HeLa cells. Structural changes unique to K562 cells and HeLa cells provide new mechanistic leads into how the structure of MALAT1 may mediate cancer in a cell-type specific manner.
Highlights
Long noncoding RNAs are involved in a wide array of biological functions in humans, including imprinting, cell differentiation, and disease proliferation [1,2]. lncRNAs regulate gene expression through multiple mechanisms, including alternative splicing [3], binding transcription factors [4,5], and binding microRNAs [6]
WT1hicloentsheenmsuasjomritoydoelf,K4516.12%-MoAfLdAaTta1paogirnetesddwiviethrgtehde MfroAmLAtThe1 ncoonnsceannscuesromuosdmelo, d41e.l1, %suogfgdeasttainpgointhtsatdiwveidrgee-sdwferoempinthgecnhoanncgaensceinrouMsAmLoAdTel1, ssuegcognesdtainrgy sthtrautcwtuirdeem-swayeeopcicnugr cinhaKn5g6e2s cinellMs.ALAT1 secondary structure may occur in K562 cells
Based on the putative structural changes with respect to a working model in noncancerous cells, we hypothesize that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) possesses different secondary structures in both K562 and HeLa cells
Summary
Long noncoding RNAs (lncRNAs; all abbreviations can be found in Supplemental Table S1, “Abbreviations” tab) are involved in a wide array of biological functions in humans, including imprinting, cell differentiation, and disease proliferation [1,2]. lncRNAs regulate gene expression through multiple mechanisms, including alternative splicing [3], binding transcription factors [4,5], and binding microRNAs (miRNAs) [6]. LncRNAs can act as competing endogenous RNAs (ceRNAs) and sponge miRNAs, hindering those miRNAs from promoting degradation of their intended mRNA targets [7,8,9,10]. MiRNA binding can even promote lncRNA degradation [9]. The ability of lncRNAs to interact with other RNAs and proteins is largely mediated by secondary structure. LncRNAs can sponge miRNAs when the binding site is free of secondary structures (e.g., hairpins and pseudoknots) and/or proteins. In cancer and other human diseases, the proper functioning of lncRNAs is directly impacted by miRNAbinding events, where miRNA sponging can promote mRNA dysregulation and aberrant gene expression [11]. While the structure dictates function of RNA and proteins, the distinct functional roles of structural elements in many lncRNAs are unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
