MALAT1 is a long (~7kb), abundant, highly conserved nuclear lncRNA that is enriched in nuclear speckle domains. MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript1) serves as a model lncRNA for us to establish the connection between a ND-enriched lncRNA and cancer.
(C) SRSF1 depletion (KD) reduces MALAT1-induced tumor growth in cancer cells (Malakar et al., 2017). (B) MALAT1-overexpressed cells show enhanced tumor growth. (A) Increased lung colonization of MALAT1 overexpressed (OE) GFP +ve cells in xenograft model (Jadaliha et al., 2016). Furthermore, we observed that A-to-I editing regulates the stability of a subset of mRNA by influencing the interaction between the RNA and RNA-destabilization factors (Anantharaman et al., NAR 2017 Anantharaman et al., FEBs Lett. In the case of paraspeckles, we observed that Adenosine-to-Inosine (A-I) editing of RNA is not essential for RNA to be localized in paraspeckles (Anantharaman et al., Sci Rep 2016). We demonstrated that nuclear speckle-localized RNA and proteins display multilayer organization, and MALAT1 regulates the speckle distribution and splicing function of SR family of splicing factors (SRSFs) ( Fig. In order to understand the role of lncRNAs in various nuclear processes, we focused our efforts in understanding the role of lncRNAs enriched in nuclear domains such as nuclear speckles, paraspeckles, and nucleolus. Characterization of nuclear domain-enriched RNA-mediated gene regulatory mechanisms 1: Super-resolution imaging data reveals multi-layered organization of MALAT1 (red), U2snRNA (green) and splicing factors (SC35 blue) within the nuclear speckles (Fei et al., 2017).
Specifically, we are studying: i) how lncRNAs enriched in discrete nuclear domains (NDs) regulate gene expression through their modulation of ND and associated chromatin structure, ii) how cell cycle-regulated lncRNAs may regulate cell proliferation and cancer progression, and iii) how cancer-deregulated lncRNAs contribute tumor progression and cancer metastasis.įig. Our current research continues to dissect the role of lncRNAs in gene regulatory mechanisms. By utilizing cellular and molecular biological approaches, we have unraveled the function of several lncRNAs in mammalian cells and their involvement in cancer progression. The long-term goal of my laboratory is to understand how lncRNAs localized within nuclear domains control gene expression, particularly during cancer progression.
Further, lncRNAs show deregulated expression in tumors and their genes are often amplified or deleted in various cancers, undermining the importance of understanding the molecular and cellular roles of lncRNAs under physiological as well as pathological conditions. Nuclear lncRNAs also act as nucleation sites for the formation and/or maintenance of sub-nuclear domains (NDs). Based on studies on a handful of them, we learned that lncRNAs regulate vital cellular processes by functioning as ‘scaffolds’ or ‘guides’ or ‘sponges’ to modulate protein-protein or protein-DNA or protein-RNA interactions, or as ‘enhancer RNAs’ to regulate gene expression. Although genetic studies have unraveled the function of a subset of these lncRNAs in key cellular processes, we still lack mechanistic insights into the role of most lncRNAs. The human genome encodes thousands of long noncoding RNA (lncRNA) genes.
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