Requirements for epigenetic inheritance of heterochromatin in fission yeast
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CitationShipkovenska, Gergana. 2020. Requirements for epigenetic inheritance of heterochromatin in fission yeast. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractThe inheritance of epigenetic traits, phenotypes which are not encoded in the genome of the cell, is universal across prokaryotes, fungi, animals and plants. Epigenetic traits can be inherited via DNA-binding proteins, RNAs, chemical modifications and even cytoplasmic proteins. In one mode of epigenetic inheritance, known as heterochromatin inheritance, modifications of DNA and the DNA-bound histone proteins bring about heritable silencing of gene expression from the underlying DNA sequence, which can persist over many cell divisions.
In the fission yeast Schizosaccharomyces pombe, heterochromatin forms broad domains of histone H3 Lysine 9 methylation (H3K9me) at the pericentromeres, telomeres, ribosomal DNA repeats and the mating type locus. Heterochromatin formation at these domains is nucleated by proteins which bind DNA or small noncoding RNAs and recruit the histone methyltransferase Clr4(Suv39h) to catalyze H3K9me on nucleosomes. H3K9me then spreads away from the sites of nucleation via a mechanism known as read-write: Clr4 binds pre-existing H3K9me and catalyzes the methylation of adjacent nucleosomes. These H3K9me-containing domains recruit downstream effectors, which contribute to the maturation of heterochromatin and the silencing of genes within its borders. These domains of H3K9me are heritable and persist over hundreds of generations.
In the present thesis I set out to identify what cellular factors are involved in the inheritance of heterochromatin in fission yeast. I performed a genome-wide screen for factors essential for the inheritance of an ectopic heterochromatic domain. I isolated mutations in several complexes, including components of the replication fork and the Clr4-containing CLRC complex. In addition, I identified a new and unexpected function in heterochromatin inheritance for an RNA processing complex, previously known to play a role in ribosome biogenesis. I demonstrated that this complex, named the rixosome after one of its principal components Rix1, localizes to both ectopic and endogenous heterochromatic domains, degrades heterochromatic RNAs and enables the spreading and inheritance of H3K9me by read-write over active transcription units.
This work elucidates the determinants of heterochromatin inheritance in fission yeast, identifies a role for a conserved RNA-degradation complex in heterochromatic gene silencing and suggests that RNA clearance is crucial for the stability and inheritance of heterochromatic domains.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365960
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