JCSMR School Seminar Series-Mechanism for RNA-mediated regulation of the histone methyltransferase Polycomb repressive complex 2 (PRC2)

Chen Davidovich, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, VIC, 3800, and EMBL-Australia and the ARC Centre of Excellence in Advanced Molecular Imaging, Clayton, VIC, 3800

Interactions between epigenetic modifiers and long noncoding RNAs or mRNAs were widely reported. Yet, functional studies to elucidate how, or if, such epigenetic modifiers are regulated by their RNA binding partners are often complicated by promiscuous RNA binding. The polycomb repressive complex 2 (PRC2) is a histone methyltransferase that trimethylates K27 of histone H3 to produce the H3K27me3 mark: an epigenetic mark that is essential for the maintenance of the repressed chromatin state of thousands of genes during development. PRC2 binds thousands of coding and noncoding transcripts, which were proposed to either recruit it to target genes for repression, or to evict PRC2 upon gene expression.

We combined biochemical and biophysical approaches in vitro with analyses of epigenomics data for protein-RNA (RIP-seq and fRIP-seq) and protein-DNA (ChIP-seq) interactions in vivo to identify how PRC2 recognises its target transcripts. This has led us to discover that multiple short tracts of consecutive guanines largely increase the affinity of PRC2 to RNA in vitro and significantly associate with PRC2 binding sites on RNA transcripts in cells. Cross-linking experiments confirmed direct interactions between RNA and four PRC2 protein subunits. In vivo, DNA sequences coding for PRC2-binding RNA motifs are enriched at PRC2-binding sites on chromatin and H3K27me3-modified nucleosomes, provide a means for RNA-mediated regulation of PRC2. More data will be discussed from our on-going attempts to understand how the polycomb machinery is regulated, combining classical biophysics and biochemistry with cutting edge approaches in structural and molecular biology.

Associate Professor Chen Davidovich has been an EMBL-Australia Group Leader in Monash University since October 2015. His lab is focused on structure-function study of gene regulation by polycomb group proteins.

In 2010 he obtained his PhD from the Weizmann Institute of Science, Israel, where he identified mechanisms for resistance and cross-resistance of bacteria to ribosomal antibiotics, in the lab of Professor Ada Yonath. While solving crystal structures of ribosome complexes, he was fascinated by RNA-protein interactions. Therefore, he continued to a postdoc with Prof. Tom Cech, at the University of Colorado, Boulder. There, he entered into the new and wild field of long-noncoding RNAs (lncRNAs). At the time, lncRNAs were already proposed to regulate epigenetic modifiers, although mechanisms were still vague. During his postdoc, he focused on the histone methyltransferase polycomb repressive complex 2 (PRC2); the most studied epigenetic modifier in the context of RNA-mediated epigenetic regulation. He was the first to quantify the affinity and specificity of PRC2 to RNA and provided the first evidence for promiscuous RNA binding by PRC2: an observation that shifted the paradigm on how PRC2 is regulated by RNA. As a group leader at Monash University, through a collaboration with his previous team in CU Boulder, he discovered the binding motif for PRC2 within RNAs. This finally explained the abundance of binding sites of PRC2 throughout the transcriptome, including both lncRNAs and mRNAs, and provided a means for RNA-mediated regulation of PRC2.

For his studies, Chen Davidovich received numerous honours and awards, including the competitive Adams Scholarship of the Israeli Academy for PhD students, the Teva Prize of the Israel Society for Biochemistry and Molecular Biology for a PhD Student, the Ziva Berkovitch-Yellin Award of the Israel Crystallographic Association for a Graduate Student, the Springer Thesis Award, the prestigious Rothschild Postdoctoral Fellowship, the Fulbright Postdoctoral Fellowship and the Ilan Ramon Award for an outstanding Fulbright Fellow in Exact Sciences. He is currently an EMBL-Australia Group Leader at Monash University.

Date & time

12–1pm 13 October 2017

Location

The Finkel Lecture Theatre, The John Curtin School of Medical Research, Building 131 Garran Road, ANU

Contacts

 Linda Tempra

Updated:  21 September 2017/Responsible Officer:  Director, JCSMR/Page Contact:  Web Manager