Transcription Regulation, One Molecule at a Time
January 14, 2025 @ 15:00 – 16:00 CET
Speaker: Arnaud Krebs, PhD, EMBL Heidelberg
Abstract
Transcription factors (TFs) bind at cis-regulatory elements (CREs) such as enhancers and promoters to activate transcription. In higher eukaryotes, chromatin presents a physical barrier that needs to be overcomedby TFs to access their DNA recognition motifs and activate transcription. Cooperativity is assumed to be a key mechanism for TFs to outcompete nucleosomes. Yet, the contribution of individual TFs to chromatin accessibility at CREs, and how their functions are assembled is currently not understood.
Current bulk assays used to map TF occupancy average binding events arising from millions of individual cells, not informing on the potential cooperativity and the antagonisms that organize their binding at CRE. To move beyond this boundary, we developed Single Molecule Footprinting (SMF) to quantify the binding of TFs at mouse regulatory regions. The method allows to simultaneously measure the occurrence of multiple TFs, nucleosomes and DNA methylation on individual molecules genome-wide.
I will illustrate how we leveraged this new layer of information to understand mechanisms of TF cooperativity and dissect the basic assembly rules used by TFs to open chromatin at CREs. Moreover, I will elaborate on our efforts to leverage long-read sequencing to study the coordination of regulatory processes between enhancers and promoters that regulate the same gene.
Relevant publications:
Single-molecule footprinting identifies context-dependent regulation of enhancers by DNA methylation. Kreibich E,. et al. Molecular Cell. 2023
Single molecule occupancy patterns of transcription factors reveal determinants of cooperative binding in vivo; Sönmezer, C, et al. Molecular Cell. 2021.
Studying transcription factor function in the genome at molecular resolution. Krebs, AR, Trends in Genetics. 2021
Biography
Arnaud Krebs runs a lab in functional genomics at EMBL with a focus on the study of gene regulation mechanism.
In his lab a new method was developed to perform single-molecule footprinting (SMF), a methodology to quantify protein–DNA contacts at the level of single DNA molecules and they were able to quantify the patterns of occupancy of transcription factors. The lab also revealed principles about the combinatorial action of transcription factors at regulatory regions. Using their single-molecule footprinting approach they identified that the binding of TFs on individual DNA molecules is influenced by DNA methylation.
The lab has a strong reputation to study the multiple layers of regulatory information by developing high-throughput experimental and computational strategies.
Short biosketch
- ERC CoG investigator 2023.
- Since January 2018 – Group leader at EMBL Genome Biology Unit.
- Ambizione independent fellow at the FMI, Basel, Switzerland.
- Postdoctoral research at the Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland. Advisor: Dirk Schübeler
- PhD, 2011, IGBMC, Strasbourg, France. Advisor: Laszlo Tora
- Masters in Molecular Biology (Uni Nancy, France) and Bioinformatics (Uni Pierre and Marie Curie, Paris)
The seminar will be followed by a fika (coffee break) where young scientists (PhD students and postdocs) can meet the speaker and ask questions about the seminar and his scientific career.
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