Abstract
Posttranscriptional gene regulation by Adenylate Uridylate (AU) rich element RNA binding protein, Elavl1 has been implicated in embryonic development as well as progenitor cell differentiation. Elavl1 binds to hundreds of cellular messenger RNAs predominantly through interactions with AU-rich elements (AREs) found in the untranslated regions (UTRs) and functions by regulating their stability. Biological functions of Elavl1 during osteogenic differentiation of bone marrow derived mesenchymal stem cells is not well-understood. Here we report that specific knockdown of nuclear localized Elavl1 by RNA interference in multipotent BMSCs led to increased osteogenic differentiation. Differential gene expression analysis following unbiased total RNA sequencing upon Elavl1 depletion during osteogenic differentiation of BMSCs showed increased levels of multiple mRNAs that are involved in extracellular matrix organization. We further show that many of these mRNAs contain Elavl1 binding consensus motifs that are preserved in their 3′ UTRs. RNA stability analyses indicated that depletion of Elavl1 prolongs the steady state RNA levels of several of these mRNAs. Together, our data points to Elavl1 mediated negative regulation of multiple genes involved in ECM organization that play a functional role in MSC osteogenic differentiation.
Highlights
Several sequence non-specific RNA binding proteins play key roles during RNA biogenesis, processing, transport and stability (Lelli et al, 2012; Corbett, 2018; Hentze et al, 2018)
As Elavl1 protein can exhibit nucleo-cytoplasmic shuttling under certain stimuli, we evaluated the localization of Elavl1 during osteogenic and adipogenic differentiation
Stable reduction of Elavl1 transcript levels were further confirmed upon osteogenic differentiation of W-20 (Figure 1G) and in ST-2 MSCs (Supplementary Figures 2A,B)
Summary
Several sequence non-specific RNA binding proteins play key roles during RNA biogenesis, processing, transport and stability (Lelli et al, 2012; Corbett, 2018; Hentze et al, 2018). Elavl (embryonic lethal-abnormal vision like 1) is one of the four highly conserved members of ELAV family proteins that play important roles in gene regulation with high affinities for U- and AU- rich sequence (ARE) containing RNAs (Simone and Keene, 2013). Elavl has important roles in regulation of RNA stability in multiple tissues generally via interactions with AU rich elements in the 3′UTRs of messenger RNAs (Lebedeva et al, 2011; Mukherjee et al, 2011). Elavl is indispensable in progenitor cells with functions in both survival and proliferation In mouse, both prenatal as well post-natal deletion of Elavl is lethal. In this study, using mouse bone marrow derived mesenchymal stem cells (BMSCs), we demonstrate that selective depletion of nuclear localized Elavl negatively regulates osteogenic differentiation, controls expression levels and stability of several AU rich element containing mRNAs associated with extracellular matrix organization
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