Studies on Silencing

Basic Sciences

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Abstract

<B>Research</b>:<BR><BR>The Developmental Genetics Section is mainly interested in the genetics and molecular biology of gene silencing and mating-type switching in <I>Schizosaccharomyces pombe</i>. In this yeast, the mating-type region consists of three loci called <I>mat1</i>, <I>mat2</i>, and <I>mat3</i>. The <I>mat2</i> and <I>mat3</i> loci are always silent and only act as donors of genetic information required for switching the transcriptionally active <I>mat1</i> locus.<BR><BR><B>Studies on Silencing</b><BR><BR>We previously found that silencing mechanism involves a chromosomally heritable epigenetic alteration, presumably of chromatin associated with the <I>mat</i> region. In fission yeast, an epigenetic imprint marking the mating-type (<I>mat2/3</i>) region contributes to inheritance of the silenced state, but the nature of the imprint is not known. We show that a chromodomain-containing swi6 protein is a dosage-critical component involved in imprinting the <I>mat</i> locus. The establishment and maintenance of the imprint are tightly coupled to the recruitment and the persistence of swi6 at the <I>mat2/3</i> region during mitosis as well as meiosis. Remarkably, swi6p remains bound to the <I>mat2/3</i> interval throughout the cell and itself seems to be a component of the imprint. Our analyses suggest that the unit of inheritance at the <I>mat2/3</i> 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 required functional Atf1/Pcr1, ATF-CREB family proteins, but not the RNA-interference Dcr1, Ago1, or Rdp1 factors, previously implicated in silencing. Our work on will continues to define the genetic determinants of silencing. This work has direct implication for explaining eucaryotic cellular differentiation and for cancer development as disruption of epigenetic controls constitutes a prominant mechanism of unwanted cellular growth.