Prof. Eva Nogales
Title: Molecular mechanisms regulating the gene silencer PRC2
Bio:
Dr. Nogales is a Howard Hughes Medical Institute investigator; a Professor of Biochemistry and Molecular Biology at the University of California, Berkeley; and Senior Faculty Scientist at the Lawrence Berkeley National Laboratory. She obtained her B.S. degree in physics from the Universidad Autonoma de Madrid (Spain). She did her thesis work at the Synchrotron Radiation Source (U.K.), under the supervision of Joan Bordas, on the structural dynamics of tubulin assembly, earning a Ph.D. degree from the University of Keele. Her work in Kenneth Downing’s group at the Lawrence Berkeley National Laboratory involved the use of electron crystallography to determine the high-resolution structure of tubulin.
(cr: https://cryoem.berkeley.edu/people/eva-nogales/)
Abstract:
Polycomb repressive complex 2 (PRC2) is an epigenetic regulator responsible for the trimethylation of histone H3 at lysine 27. This chromatin mark leads to the silencing of key genes, an essential process for both embryonic development and the maintenance of cell identity. PRC2 function is regulated through several mechanisms, including its association with various accessory proteins and its recognition of different histone posttranslational modifications. We have used cryo-EM to shed light into the different molecular mechanisms that regulate the activity of PRC2, included how the complex can be recruited by PRC1-deposited H2A119Ub, or how its activity is stimulated by its own H3K27me3 product, leading to spread of the mark. This spreading is thought to be limited by the inhibition of PRC2 activity on nucleosomes containing H3K36me3 and H3K4me3 modifications, which localize to sites of active transcription, by a currently unknown mechanism. I will show how our cryo-EM studies reveal that the inhibition involves changes in distinct structural elements within PRC2 or at the PRC2-nucleosome interface. Additionally, EZH2, the PRC2 subunit with methyltransferase activity, has been shown recently to be automethylated in cis, leading to increased enzymatic activity. We have now seen that, in a novel chromatin- and automethylation-dependent manner, PRC2 dimerizes so that an automethylated inactive PRC2 complex serves as an allosteric activator of a second substrate-engaged PRC2. Finally, we have most recently characterized PRC2 complexes with alternative cofactor proteins and shown that they give rise to different architectures.
Host: Prof. Silvia Cavagnero