title: Downregulation of rRNA transcription triggers cell differentiation.
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.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Kuroda
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan; Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishimoto
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Changshan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Kimura
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics*; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics; D012318:RNA Polymerase I / Q000235:genetics; D012335:RNA, Ribosomal / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; D034741:RNA, Small Interfering; D014157:Transcription Factors; D012318:RNA Polymerase I