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Abstract
The RNA decay pathway plays key regulatory roles in cell identities and differentiation processes. Although adipogenesis is transcriptionally and epigenetically regulated and has been thoroughly investigated, how RNA metabolism that contributes to the stability of phenotype-shaping transcriptomes participates in differentiation remains elusive. In this study, we investigated Ddx6, an essential component of processing bodies (PBs) that executes RNA decay and translational repression in the cytoplasm and participates in the cellular transition of reprogramming. Upon adipogenic induction, Ddx6 dynamically accumulated to form PBs with a binding partner, 4E-T, at the early phase prior to emergence of intracellular lipid droplets. In contrast, preadipocytes with Ddx6 knockout (KO) or 4E-T knockdown (KD) failed to generate PBs, resulting in significant suppression of adipogenesis. Transcription factors related to preadipocytes and negative regulators of adipogenesis that were not expressed under adipogenic stimulation were maintained in Ddx6-KO and 4E-T-KD preadipocytes under adipogenic induction. Elimination of Dlk1, a major negative regulator of adipogenesis, in 3T3L1 Ddx6-KO cells did not restore adipogenic differentiation capacity to any extent. Similar to murine cells, human primary mesenchymal stem cells, which can differentiate into adipocytes upon stimulation with adipogenic cocktails, required DDX6 to maturate into adipocytes. Therefore, RNA decay of the entire parental transcriptome, rather than removal of a strong negative regulator, could be indispensable for adipogenesis.
Highlights
Cellular identity is driven by genomic, epigenomic, transcriptomic, and proteomic heterogeneity
processing bodies (PBs) and the expression of mesenchymal genes during adipogenesis The preadipocyte cell line 3T3L1 was used in this study to investigate the role of RNA metabolism in adipogenesis induced by standard differentiation cocktails[24]
RNA decay occurs in PBs, which are specialized membraneless organelles for RNA metabolism that are involved in the onset of differentiation of stem cells[8]; PBs of 3T3L1 cells during adipogenesis were visualized by staining with Ddx[6], an essential protein of PBs
Summary
Cellular identity is driven by genomic, epigenomic, transcriptomic, and proteomic heterogeneity. In addition to RNA decay, control of mRNA levels is Official journal of the Cell Death Differentiation Association. The molecular machinery that silences targeted mRNAs via RNA decay or translational repression is composed of the RNAinduced silencing complex (RISC)[9], which consists of microRNAs that recognize their target mRNAs through partial complementarity with the help of Argonaute proteins[10]. For RNA metabolism, cells contain membraneless organelles, which are flexible biological condensates composed of many proteins. Such organelles include various ribonucleoprotein (RNP) granules; processing bodies (PBs), which are maintained by essential factors including Ddx6, 4E-T, and LSM14A16; and stress granules in the cytoplasm. Along with RISCs, the spatial and temporal association or dissociation of these effector molecules, such as Ddx[6] and 4E-T, enables fine-tuning of the transcriptome to ensure that it is appropriate for the environment and that it maintains homeostasis in the body
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