Studies on Silencing

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The Developmental Genetics Section is mainly interested in the genetics and molecular biology of gene silencing and mating-type switching in Schizosaccharomyces pombe (s. pombe). In this yeast, the mating-type region consists of 3 loci: mat1, mat2, and mat3. The mat2 and mat3 loci are always silent and only act as donors of the genetic information that is required for switching the transcriptionally active mat1 locus. Studies on Silencing. Previously, we found that the silencing mechanism involves a chromosomally heritable epigenetic alteration, presumably of chromatin associated with the mat region. In fission yeast, an epigenetic imprint marking the mating-type (mat2/3) region contributes to inheritance of the silenced state, but the nature of this imprint is unknown. We have shown that a chromodomain-containing swi6 protein is a dosage-critical component involved in imprinting the mat locus. The establishment and maintenance of the imprint are tightly coupled to the recruitment and persistence of swi6 at the mat2/3 region during mitosis as well as meiosis. Remarkably, swi6p remains bound to the mat2/3 interval throughout the cell and itself seems to be a component of the imprint. Our analyses suggest that the unit of inheritance at the mat2/3 locus comprises the DNA plus the associated swi6 protein complex. Interestingly, the silenced domain is bracketed by 1.2KB inverted repeat sequences that block spreading of heterochromatin to adjoining regions of chromosome. We have discovered that mutations in deoxyribonucleotide biosynthesis cause spreading of silencing across these heterochromatin barriers. The spreading of heterochromatin across barriers requires functional Atf1/Pcr1, ATF-CREB family proteins, but not the RNA-interference Dcr1, Ago1, or Rdp1 factors that were previously implicated in silencing. Our work continues to define the genetic determinants of silencing and has direct implications for explaining eukaryotic cellular differentiation and cancer development as a disruption of epigenetic controls, constituting a prominent mechanism of unwanted cellular growth.