Abstract
Responding to various stimuli is indispensable for the maintenance of homeostasis. The downregulation of ribosomal RNA (rRNA) transcription is one of the mechanisms involved in the response to stimuli by various cellular processes, such as cell cycle arrest and apoptosis. Cell differentiation is caused by intra- and extracellular stimuli and is associated with the downregulation of rRNA transcription as well as reduced cell growth. The downregulation of rRNA transcription during differentiation is considered to contribute to reduced cell growth. However, the downregulation of rRNA transcription can induce various cellular processes; therefore, it may positively regulate cell differentiation. To test this possibility, we specifically downregulated rRNA transcription using actinomycin D or a siRNA for Pol I-specific transcription factor IA (TIF-IA) in HL-60 and THP-1 cells, both of which have differentiation potential. The inhibition of rRNA transcription induced cell differentiation in both cell lines, which was demonstrated by the expression of the common differentiation marker CD11b. Furthermore, TIF-IA knockdown in an ex vivo culture of mouse hematopoietic stem cells increased the percentage of myeloid cells and reduced the percentage of immature cells. We also evaluated whether differentiation was induced via the inhibition of cell cycle progression because rRNA transcription is tightly coupled to cell growth. We found that cell cycle arrest without affecting rRNA transcription did not induce differentiation. To the best of our knowledge, our results demonstrate the first time that the downregulation of rRNA levels could be a trigger for the induction of differentiation in mammalian cells. Furthermore, this phenomenon was not simply a reflection of cell cycle arrest. Our results provide a novel insight into the relationship between rRNA transcription and cell differentiation.
Highlights
The nucleolus is a major component of the nucleus and it is the site of ribosome biogenesis
Considering that the downregulation of ribosomal RNA (rRNA) transcription is involved in various cellular processes [6,7,8,9], it is possible that downregulated rRNA levels induce differentiation
We investigated whether the downregulation of rRNA levels induced differentiation using HL-60 and THP-1 cells
Summary
The nucleolus is a major component of the nucleus and it is the site of ribosome biogenesis. The processes involved in ribosome generation require the transcription of ribosomal DNA (rDNA) genes by RNA polymerase I (Pol I). The initially transcribed ribosomal RNA (rRNA) is 47S rRNA, i.e., the so-called prerRNA, which is cleaved to form the mature 28S, 18S, and 5.8S rRNAs. the mature rRNAs are assembled with ribosomal proteins to generate functional ribosomes [1]. The mature rRNAs are assembled with ribosomal proteins to generate functional ribosomes [1] During these steps, the rate of rRNA transcription by Pol I is a major control point for ribosome biogenesis [2]. RRNA transcription requires the synergistic actions of two DNA-binding factors, the upstream binding factor (UBF) and the promoter selectivity factor (SL1/TIF-IB), both of which are essential for the recognition of a rDNA promoter by Pol I. The activity of TIF-IA is regulated by phosphorylation and it modulates the rate of rRNA transcription [3]
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