ja9b02321_si_001.pdf (3.54 MB)
Nucleation and Propagation of Heterochromatin by the Histone Methyltransferase PRC2: Geometric Constraints and Impact of the Regulatory Subunit JARID2
journal contribution
posted on 2019-09-16, 20:44 authored by Eva J. Ge, Krupa S. Jani, Katharine L. Diehl, Manuel M. Müller, Tom W. MuirPolycomb
Repressive Complex 2 (PRC2) catalyzes mono-, di-, and
trimethylation of lysine 27 on histone H3 (H3K27me1–3) to control
expression of genes important for differentiation and maintenance
of cell identity. PRC2 activity is regulated by a number of different
inputs, including allosteric activation by its product, H3K27me3.
This positive feedback loop is thought to be important for the establishment
of large domains of condensed heterochromatin. In addition to other
chromatin modifications, ancillary subunits of PRC2, foremost JARID2,
affect the rate of H3K27 methylation. Many gaps remain in our understanding
of how PRC2 integrates these various signals to determine where and
when to deposit H3K27 methyl marks. In this study, we utilize designer
chromatin substrates to demonstrate that propagation of H3K27 methylation
by the PRC2 core complex has geometrically defined preferences that
are overridden by the presence of JARID2. Our studies also show that
phosphorylation of JARID2 can partially regulate its ability to stimulate
PRC2 activity. Collectively, these biochemical insights further our
understanding of the mechanisms that govern PRC2 activity, and highlight
a role for JARID2 in de novo deposition of H3K27me3-containing
repressive domains.