The role of DNA topology in epigenetic regulation by Polycomb proteins

About the Project

Project Description: Correct use of the genome is at the heart of cell function and development. The primary sequence of DNA holds its essential information, yet the organization and structure of DNA also encode information. This includes the packaging of DNA into chromatin, and the vast array of chromatin regulatory mechanisms. It also includes the topological state of DNA, which affects the genome at multiple scales—from protein-DNA interactions, local and large-scale chromatin structure to transcription and DNA replication. Topology also influences the propensity of DNA to form structures beyond the canonical B-form double helix (R-loops, G-quartets, etc.). As methods to study DNA physical properties in vitro and in cells have increased in resolution, a picture of DNA topology and non-canonical DNA structures as a “hidden layer” of regulatory information is emerging. This invites a fresh look at how chromatin and nucleic acid regulation are integrated including by classical “chromatin” regulators like the Polycomb Group (PcG) proteins.

Initially described in Drosophila, PcG proteins, their biochemical properties, and their essential regulatory functions have been identified in organisms from plants to humans. The hallmark activity of the PcG system is the ability to mediate epigenetic memory of gene repression across cell divisions. PcG proteins assemble into complexes, most notably Polycomb Repressive Complex 1(PRC1) and 2 (PRC2). PRC1 and PRC2 can modify histones (H2A119Ub and H3K27me, respectively) and regulate chromatin architecture. Although it is widely assumed that all PcG functions reflect chromatin activities, both complexes also bind DNA and RNA. In PRC1, large intrinsically disordered regions (IDRs) are important for nucleic acid binding. Both PRC1 and PRC2 are implicated in transcription regulation but have also been shown to contribute to DNA repair and cell cycle events. Our global hypothesis is that PcG proteins depend on both nucleic acid-based and chromatin activities to regulate genome organization, gene expression, and genome stability.The long-term objectives of this research program are to understand: i) the role of DNA topology and non-canonical nucleic acid structures in epigenetic memory and genome maintenance by the PcG; ii) the function of IDRs in chromatin proteins and how their evolution imparts flexibility on conserved systems, We use in vitro reconstitution coupled with genomics and cell-based assays in the relatively simple Drosophila model system, where epigenetic memory by the PcG is best understood. The objective of this PhD project is to investigate a novel nucleic acid based activity of an IDR in PRC1 that connects the PcG directly to DNA topology.

Your profile

We are open to candidates with different experience, and to adapting training and projects to the student. We encourage you to apply if you have:

• A degree in biochemistry, biophysics or related discipline, or in chemistry, engineering, physics or related fields with a strong interest in learning biology (MSc level)
• A high level of motivation and curiosity
• A collaborative nature and ability to work independently and in a team

What we offer:

• A chance to work at the IRCM, a diverse internationally recognized research institute affiliated with the University of Montreal
• A chance to live in Montreal, a vibrant, cosmopolitan city with a thriving research and cultural environment
• An opportunity to work in a bilingual environment—we are a French-speaking institute, but interactions in the Francis lab occur mainly in English
• The chance to work in a lab that values diversity, technical skill, intellectual engagement, collaboration and curiosity, and is committed to scientific excellence and personal development of all members
• Our lab and our institution are committed to equity, diversity and inclusion as part of the path to excellence

About the Francis lab:

Our lab is interested in epigenetic mechanisms, with a particular focus on transcription memory and how chromatin-based information is passed through the cell cycle. Some of our recent publications are below, and more information can be found on our website https://www.francis-lab-epigenetics.ca/:

1. Gemeinhardt, T.M.^* Regy, R.M.^*, Phan, T.M.^*, Pal, N., Sharma, J., Senkovich, O., Mendiola, A.J., Ledterman, H.J., Henrickson, A., Lopes, D., Kapoor, U., Bihani, A., SIhou, D., Kim, Y.C., Jeruzalmi, D., Demeler, B., Kim, C.A., Mittal, J.^# & Francis, N.J.^# (2025) A disordered linker in the Polycomb protein Polyhomeotic tunes phase separation and oligomerization. Molecular Cell 85: 2128-2146. https://doi.org/10.1016/j.molcel.2025.05.008
2. Seif, E. Kang, J.J., Sasseville, C., Senkovich, O., Kaltashov, A., Boulier, E.L., Kapur, I., Kim, C.A., and Francis, N.J. (2020) Phase separation by the Sterile Alpha Motif of Polyhomeotic compartmentalizes Polycomb Group proteins and enhances their activity. Nat Commun 11,5609. https://rdcu.be/b9L1P
3. Alecki, C., Chiwara, V., Sanz, L. A., Grau, D., Pérez, O. A., Boulier, E. L., Armache, K.-J., Chédin, F., & Francis, N. J. (2020). RNA-DNA strand exchange by the Drosophila Polycomb complex PRC2. Nature Commun., 11(1), 1–14. https://rdcu.be/b3y5P

To apply: Please send your CV and cover letter to nicole.francis@ircm.qc.ca. 3 letters of recommendation will be requested if your application is pursued.