Transcriptional reprogramming in cellular quiescence

Abstract

Most cells in nature are not actively dividing, yet are able to return to the cell cycle given the appropriate environmental signals. There is now ample evidence that quiescent G0 cells are not shut-down but still metabolically and transcriptionally active. Quiescent cells must maintain a basal transcriptional capacity to maintain transcripts and proteins necessary for survival. This implies a tight control over RNA polymerases: RNA pol II for mRNA transcription during G0, but especially RNA pol I and RNA pol III to maintain an appropriate level of structural RNAs, raising the possibility that specific transcriptional control mechanisms evolved in quiescent cells. In accordance with this, we recently discovered that RNA interference is necessary to control RNA polymerase I transcription during G0. While this mini-review focuses on yeast model organisms (Saccharomyces cerevisiae and Schizosaccharomyces pombe), parallels are drawn to other eukaryotes and mammalian systems, in particular stem cells.

Keywords: Dicer; G0; RNA interference; differentiation; dormancy; epigenetics; histone; quiescence; reprogramming; stem cells; transcription.

Figure 1.

The many facets of cellular quiescence and non-dividing cells. (A) Non-dividing cells exit the cell cycle in response to specific environmental cues to enter different types of G0 states. At one end of the spectrum, microbial spores are metabolically shut-down and dormant; at the other end, cells terminally differentiate in specialized post-mitotic states (such as neurons and myocytes). There is a continuum in terms of reversibility to the cell cycle, metabolic activity and differentiation/specialization. (B) The “quiescence cycle” model proposes a progressive entry into G0, and conversely that in response to environmental signals (such as stem cell activation) G0 cells can enter a poised Galert state facilitating G0-exit.

Figure 2.

Model for the novel essential role for Dicer in RNA polymerase I release in G0. (A) In wild-type cycling cells, RNA pol I transcribes the rDNA repeats. (B) Wild-type G0 cells lower the recruitment of RNA pol I to rDNA, in part via phosphorylation of the Rrn3 initiation factor, shifting the ratio of active vs. silent rDNA repeats. Dicer contributes to RNA pol I release, although it is still unknown whether this occurs directly at the level of rRNA or via RNA pol I itself. (C) Dicer mutants in G0 are defective in RNA pol I release, resulting in accumulation of stalled RNA pol I, DNA damage, and the recruitment of the silencing CLRC/Rik1 complex at the repeat, causing a hyper-silencing of rDNA repeats via H3K9 methylation. (D) The Dicer defect is suppressed by mutants in the H3K9 methylation pathway (class 2: such as dcr1Δclr4Δ), by reducing RNA pol I transcription initiation (class 3: such as dcr1Δtbp1-D156Y), or by destabilizing RNA pol I itself (class 4: such as dcr1Δrpa12Δ). (Note: class 1 suppressors are not represented, and concern chromosomal segregation during G0-entry).