dc.description.abstract |
Heterochromatin is a minimally transcribed, densely bundled complex of DNA
and associated factors comprising large regions of the eukaryotic genome. It is essential
for chromosome stability, genome integrity, gene regulation, and the silencing of
transposons. The filamentous fungus Neurospora crassa is often employed as a model
organism to study the epigenetic regulation ofheterochromatin. In Neurospora, the
conserved scaffolding protein heterochromatin protein 1 (HP 1) binds H3 histones
marked by lysine nine trimethylation (H3K9me3) and recruits other proteins to form at
least four distinct complexes. HPl recruits the DIM-2 DNA methyltransferase, which
catalyzes DNA methylation, and the Mi-2 chromatin remodeler, which promotes
centromeric silencing. HPI is also an essential component of the HCHC complex,
which facilitates histone deacetylation, and the DMM complex, which limits aberrant
heterochromatin spreading. However, it is unclear how these disparate functions are
coordinated. We hypothesized that they are modulated by post-translational
modifications (PTMs) of HPI. Previously, we used mass spectrometry to identify HPl
sites harboring methylation, acetylation, formylation, and phosphorylation. I used
amino acid substitutions at a subset of these sites to prevent individual PTMs in vivo.
Substitutions at multiple sites were found to cause a substantial decrease in centromeric
silencing independent of DNA methylation. These results suggest that the recruitment
of Mi-2 to incipient heterochromatin may be selectively mediated by specific PTMs. |
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