Background

Most of the genetic sequence variants distinguishing individuals occur at cis-regulatory elements that control genes through the binding of Transcription Factors. Transcription Factors read DNA sequences of regulatory elements and convert this regulatory genetic information into precise gene expression programs required to define cell identity during development. Despite our extensive knowledge of the location of regulatory elements, our understanding of how these elements are read by transcription factors remains superficial. Activation of a regulatory element typically requires the coordinated action of multiple TFs. Understanding these cooperative interactions is a key to decipher the regulatory genetic information and interpret its variation between individuals.

Project

Construction of a Transcription Factor cooperativity atlas: How do Transcription Factors cooperate to make cell types?

The goal of this project is to build an atlas of the cooperative interactions occurring between TFs in multiple cell types. Modelling of the generated data will allow us to identify the general as well as cell specific principles underlying TF cooperativity at CREs. We will combine Single Molecule Footprinting (SMF) to map TF co-occupancy in multiple cell-types (Krebs lab – EMBL) with machine-learning approach to quantify TF footprints patterns at the single molecule resolution and define syntax rules underlying cooperativity (Kundaje lab – Stanford).  Do TFs exhibit cell-type specific cooperativity modules? Are they using a common set of syntax rules to cooperate? How does cooperativity impact gene expression programs that define cell identity?

References:

^{1. Avsec Ž, Weilert M, Shrikumar A, Krueger S, Alexandari A, Dalal K, Fropf R, McAnany C, Gagneur J, Kundaje A, Zeitlinger J. Base-resolution models of transcription-factor binding reveal soft motif syntax. Nat Genet. 2021 Feb 18. doi: 10.1038/s41588-021-00782-6. Epub ahead of print. PMID: 33603233.}

^{2. Sönmezer C, Kleinendorst R, Imanci D, Barzaghi G, Villacorta L, Schübeler D, Benes V, Molina N, Krebs AR. Molecular Co-occupancy Identifies Transcription Factor Binding Cooperativity In Vivo. Mol Cell. 2021 Jan 21;81(2):255-267.e6.doi: 10.1016/j.molcel.2020.11.015. Epub 2020 Dec 7. PMID: 33290745.}

Additional links:
^{https://github.com/kundajelab/bpnet
https://github.com/Krebslabrep/SingleMoleculeFootprinting}

Find out more:

Interested in finding out more about working at the interface of metabolism and organelle biology? Get in touch, we would love to hear from you!