Kota Satya K, Lim Zhu Wei, Kota Savithri B
Division of Bone and Mineral Research, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, MA, United States.
Division of Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States.
Front Cell Dev Biol. 2021 Feb 4;9:606971. doi: 10.3389/fcell.2021.606971. eCollection 2021.
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.
富含腺苷酸尿苷酸（AU）元件的RNA结合蛋白Elavl1介导的转录后基因调控与胚胎发育以及祖细胞分化有关。Elavl1主要通过与位于非翻译区（UTR）的富含AU元件（ARE）相互作用，与数百种细胞信使RNA结合，并通过调节其稳定性发挥作用。Elavl1在骨髓间充质干细胞成骨分化过程中的生物学功能尚不清楚。在此，我们报告，通过RNA干扰在多能骨髓间充质干细胞中特异性敲低核定位的Elavl1会导致成骨分化增加。在骨髓间充质干细胞成骨分化过程中Elavl1缺失后，通过无偏全RNA测序进行差异基因表达分析，结果显示参与细胞外基质组织的多种mRNA水平升高。我们进一步表明，这些mRNA中的许多在其3'UTR中含有保守的Elavl1结合共有基序。RNA稳定性分析表明，Elavl1的缺失延长了其中几种mRNA的稳态RNA水平。总之，我们的数据表明Elavl1对参与细胞外基质组织的多个基因具有负调控作用，这些基因在间充质干细胞成骨分化中发挥功能作用。
