Histone deacetylase homologs regulate epigenetic inheritance of transcriptional silencing and chromosome segregation in fission yeast.
Position-effect control at the silent mat2-mat3 interval and at centromeres and telomeres in fission yeast is suggested to be mediated through the assembly of heterochromatin-like structures. Therefore, trans-acting genes that affect silencing may encode either chromatin proteins, factors that modify them, or factors that affect chromatin assembly. Here, we report the identification of an essential gene, clr6 (cryptic loci regulator), which encodes a putative histone deacetylase that when mutated affects epigenetically maintained repression at the mat2-mat3 region and at centromeres and reduces the fidelity of chromosome segregation. Furthermore, we show that the Clr3 protein, when mutated, alleviates recombination block at mat region as well as silencing at donor loci and at centromeres and telomeres, also shares strong homology to known histone deacetylases. Genetic analyses indicate that silencing might be regulated by at least two overlapping histone deacetylase activities. We also found that transient inhibition of histone deacetylase activity by trichostatin A results in the increased missegregation of chromosomes in subsequent generations and, remarkably, alters the imprint at the mat locus, causing the heritable conversion of the repressed epigenetic state to the expressed state. This work supports the model that the level of histone deacetylation has a role in the assembly of repressive heterochromatin and provides insight into the mechanism of epigenetic inheritance.
Gene Regulation and Chromosome Biology Laboratory, ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201, USA.
S I
SI
Grewal
M J
MJ
Bonaduce
A J
AJ
Klar
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D002503:Centromere / Q000235:genetics; D020090:Chromosome Segregation / Q000502:physiology*; D015825:Chromosomes, Fungal / Q000235:genetics; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005800:Genes, Fungal / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D008540:Meiosis / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames / Q000235:genetics; D012331:RNA, Fungal / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D011995:Recombination, Genetic / Q000235:genetics; D012568:Schizosaccharomyces / Q000201:enzymology / Q000235:genetics*; D029702:Schizosaccharomyces pombe Proteins; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic / Q000502:physiology*
D018797:Cell Cycle Proteins; C115302:Clr3 protein, S pombe; C115303:Clr6 protein, S pombe; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012331:RNA, Fungal; D012333:RNA, Messenger; D029702:Schizosaccharomyces pombe Proteins; C012589:trichostatin A