Investigation of the cellular significance of long non-coding RNA NEAT1 and paraspeckles

Ruohan Li

Research output: ThesisDoctoral Thesis

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Abstract

[Truncated] The majority of the human genome is transcribed into RNA, a large componentofwhich consists of long non-coding RNAs (lncRNAs).For those lncRNAs that have been well-studied, a wide variety of mechanisms in gene regulation have been revealed. NEAT1 (nuclear paraspeckle assembly transcript 1) is a lncRNA essential for the formation and maintenance of subnuclear structures termed paraspeckles.Paraspeckles are RNA-protein complexes that function by sequestering specific nuclear proteins and mRNAsto prevent them trafficking to their functional destinations, resulting in downstream effects on gene expression.Ablation of NEAT1 and paraspeckles is important for various aspects of female fertility in mice, as well as the ability of cultured cells tocope with various types of cellular stresses.However, not much is known of the importance of NEAT1 and paraspeckles at the cellular level.Here, the main focus is to address this by systematically examining the regulation of NEAT1 expression, as well as the effect of NEAT1 on cell function.
In examining the upstream pathways that regulate NEAT1 transcription I found that as cells transition from pluripotency to a differentiated state, epigenetic silencing ofNEAT1is gradually lost, replaced with an epigenetic signature indicative of a highly active state of transcription. This explainswhy NEAT1 is expressed in differentiated, but not pluripotent cells.I also found that transcription factors associated with the humanNEAT1promoter are involved in awide range of cellular processes, thus presenting a possible mechanismNEAT1 expression is generally both ubiquitous and dynamic. Under different stress conditionsincludingserum starvation and theacidosis of culture media, NEAT1 levels and paraspeckleabundance was robustly induced in a subset of cell lines that were examined.In U2OS (human osteosarcoma cells), the upregulation of NEAT1 appeared to be primarily caused by direct transcriptional activation, mediated, at least in part by the action of p53 on theNEAT1promoter.These findings linkthe transcriptional regulation of NEAT1 to the well-characterized p53 stress response pathway, and helps explain why NEAT1 expression is highly dynamic under conditionsthat are potentially stressful to cells.
Original languageEnglish
QualificationDoctor of Philosophy
Publication statusUnpublished - 2016

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