Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
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Edited by Fred M. Winston, Harvard Medical School, Boston, MA, and approved July 5, 2016 (received for review February 1, 2016)
Significance
The yeast HO gene is under complex regulation during the cell cycle. Swi5 binds to the promoter during the M phase to promote later activation but is absent when the gene is activated in late G1. Thus cells “remember” the effects of Swi5 at the promoter, and this is especially important during prolonged G1 arrest due to nutrient deprivation. Promoter “memory” consists of SBF factor and Mediator bound at the promoter. However, this promoter memory is lost in cells arrested in G1 by pheromone exposure. We show that this memory loss occurs by transcription through the promoter, displacing bound SBF, thereby erasing the memory. Thus, factors at a promoter can constitute memory of prior decisions, and displacement by transcription can remove this memory.
Abstract
The yeast HO endonuclease is expressed in late G1 in haploid mother cells to initiate mating-type interconversion. Cells can be arrested in G1 by nutrient deprivation or by pheromone exposure, but cells that resume cycling after nutrient deprivation or cyclin-dependent kinase (CDK) inactivation express HO in the first cell cycle, whereas HO is not expressed until the second cycle after release from pheromone arrest. Here, we show that transcription of a long noncoding RNA (lncRNA) mediates this differential response. The SBF and Mediator factors remain bound to the inactive promoter during arrest due to CDK inactivation, and these bound factors allow the cell to remember a transcriptional decision made before arrest. If the presence of mating pheromone indicates that this decision is no longer appropriate, a lncRNA originating at –2700 upstream of the HO gene is induced, and the transcription machinery displaces promoter-bound SBF, preventing HO transcription in the subsequent cell cycle. Further, we find that the displaced SBF is blocked from rebinding due to incorporation of its recognition sites within nucleosomes. Expressing the pHO-lncRNA in trans is ineffective, indicating that transcription in cis is required. Factor displacement during lncRNA transcription could be a general mechanism for regulating memory of previous events at promoters.
Footnotes
- ↵1To whom correspondence should be addressed. Email: david.stillman{at}path.utah.edu.
Author contributions: R.M.Y., N.C.E., and D.J.S. designed research; Y.Y., R.M.Y., E.B.C., and N.C.E. performed research; Y.Y., R.M.Y., E.B.C., and D.J.S. analyzed data; and R.M.Y., N.C.E., and D.J.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1601793113/-/DCSupplemental.
lncRNA synthesis disrupts promoter memory
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