Editors' ChoiceMOLECULAR BIOLOGY

DNA memories for mating

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Sci. Signal.  30 Aug 2016:
Vol. 9, Issue 443, pp. ec199
DOI: 10.1126/scisignal.aai8907

The yeast Saccharomyces cerevisiae can live as haploid cells or can respond to mating pheromone to mate and become diploid. The endonuclease HO initiates mating type interconversion through DNA recombination. Yeast arrested in G1 of the cell cycle because of nutrient deprivation express HO during the first cell cycle after release from arrest, whereas yeast arrested by pheromone signaling express HO in the second cell cycle after arrest. Thus, the DNA “remembers” the cause of the arrest. The 5ʹ upstream region of the gene for HO is unusually long relative to the size of other yeast genes, contains two upstream regulatory regions that bind transcriptional coactivators and chromatin remodeling complexes, and also encodes a long noncoding RNA (lncRNA). Yu et al. identified a response element for the pheromone-responsive transcription factor Ste12 that was required for expression of the pHO-lncRNA. Yeast with mutant versions of this response element did not express the pHO-lncRNA and expressed HO in the first cell cycle after release from mating pheromone. The chromatin-remodeling complex SBF mediates nucleosome eviction to enable gene expression. Whereas SBF was not bound to the 5ʹ upstream sequence of HO in yeast arrested by mating pheromone, it remained bound in pheromone-arrested yeast with the mutated Ste12 response element in the HO 5ʹ upstream sequence. To test if transcription of the pHO-lncRNA was necessary for displacement of SBF, the authors introduced a premature stop codon such that the lncRNA would terminate before the first upstream regulatory region in the HO gene. SBF remained bound in pheromone-arrested yeast containing the premature stop codon, and experiments with diploid yeast showed that the lncRNA did not function in trans but had to be expressed in cis to suppress HO expression. Introduction of chimeric gene sequences to alter nucleosome binding and depletion showed that even when pHO-lncRNA was properly expressed in response to mating pheromone, nucleosome depletion enabled the persistent binding of SBF and inappropriate first cell cycle expression of HO. Thus, the authors propose that just the process of transcribing a lncRNA can alter chromatin structure such that expression of the protein-coding portion of the gene is repressed as nucleosomes rebind following lncRNA transcription.

Y. Yu, R. M. Yarrington, E. B. Chuong, N. C. Elde, D. J. Stillman, Disruption of promoter memory by synthesis of a long noncoding RNA. Proc. Natl. Acad. Sci. U.S.A. 113, 9575–9580 (2016). [PubMed]