Histone deacetylases and their co-regulators in Schizosaccharomyces pombe

The DNA in every eukaryotic cell is wrapped around eight core histones to form the nucleosome. Therefore all events that involve DNA must also involve chromatin and nucleosomes. By regulating chromatin structure the cell can regulate the reactivity of the DNA. One of the most common ways of altering nucleosomes is the acetylation of lysine residues. Two enzymes are required to maintain the correct equilibrium for optimal cell growth: histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs). In general, histone hypoacetylation is correlated with transcriptional inactivation, while hyperacetylation is correlated with active gene transcription.

In Schizosaccharomyces pombe, mating type loci are silenced. Deletion of HDAC Hos2 had previously been shown to slightly increase silencing at the mating type locus. To assess whether any other HDAC was necessary for mating type silencing, cells were treated with HDAC poison Trichostatin A (TSA). TSA was found to cause a mild derepression of the mating type locus, indicating that another HDAC was responsible for silencing in this region. The RNA interference nuclease Dcr1 was later identified, and showed to degrade double stranded RNA into small nucleotide fragments. Deletion of dcr1 caused chromosome segregation defects and derepression of centromeric silencing.

Rpd3 in S. cerevisiae is recruited to genomic targets by interacting with co-regulator Sin3. S. pombe has three Sin3 homologs. Pst1 interacts with the HDAC Clr6, and like Clr6 is an essential gene, mutants of which display chromosome mis-segregation and derepression of centromeric silencing. Pst1 was required for centromeric cohesion, and localized to centromeres in late S phase. Thus a co-repressor paradigm could be applied to centromere silencing as well. A comparative characterization of HDACs in S. pombe showed that the HDACs had different localizations and histone specificities.

The comparison of HDACs was taken further with a genome wide expression analysis and histone density study of mutants. Results indicated that Clr6 was most often involved in promoter initiated gene repression, whereas Hos2 promoted the high expression of growth related genes by deacetylating H4K16ac in their coding regions. A class II HDAC, Clr3, was found to act cooperatively with Sir2 throughout the genome. Using a genomic approach to analyze Pst3, it was established that Clr6 and Pst3 could cooperate to negatively regulate genes by binding to their promoter regions. On the other hand, Pst3 was also involved in the up-regulation of ribosome biosynthesis genes, and could bind to the rDNA.

List of scientific papers

I. Olsson TG, Silverstein RA, Ekwall K, Sunnerhagen P (1999). "Transient inhibition of histone deacetylase activity overcomes silencing in the mating-type region in fission yeast." Curr Genet 35(2): 82-7
https://pubmed.ncbi.nlm.nih.gov/10079326

II. Provost P, Silverstein RA, Dishart D, Walfridsson J, Djupedal I, Kniola B, Wright A, Samuelsson B, Radmark O, Ekwall K (2002). "Dicer is required for chromosome segregation and gene silencing in fission yeast cells." Proc Natl Acad Sci U S A 99(26): 16648-53. Epub 2002 Dec 13
https://pubmed.ncbi.nlm.nih.gov/12482946

III. Silverstein RA, Richardson W, Levin H, Allshire R, Ekwall K (2003). "A new role for the transcriptional corepressor SIN3; regulation of centromeres." Curr Biol 13(1): 68-72
https://pubmed.ncbi.nlm.nih.gov/12526748

IV. Bjerling P, Silverstein RA, Thon G, Caudy A, Grewal S, Ekwall K (2002). "Functional divergence between histone deacetylases in fission yeast by distinct cellular localization and in vivo specificity." Mol Cell Biol 22(7): 2170-81
https://pubmed.ncbi.nlm.nih.gov/11884604

V. Wiren M, Silverstein RA, Sinha I, Walfridsson J, Lee HM, Laurenson P, Pillus L, Robyr D, Grunstein M, Ekwall K (2005). "Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast." EMBO J 24(16): 2906-18. Epub 2005 Aug 4
https://pubmed.ncbi.nlm.nih.gov/16079916

VI. Silverstein RA, Walfridsson J, Bonilla C, Ekwall K (2007). "Sin3 homolog Pst3 a key factor in nucleolar function." Current Biology (Submitted)