Biochemistry of Gene Regulation

Biochemistry of eukaryotic Gene Regulation
Figure 1. The unexplored sequence of eukaryotic Transcription factors. Alphafold prediction of an exemplary transcription factor sequence (Msn2 from yeast). Red lines indicate protein regions without structure and of mostly unknown function
Group leader
2023-01_jonas
Felix Jonas
Assistant Professor of Biochemistry
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Gene regulation – the sum of mechanisms allowing living organisms to express different phenotypes without changing the underlying genome – underlies many physiological processes like cell differentiation during development or cancer metastasis. It further drives most of the evolutionary changes between species. Years of intense research has revealed the major players in eukaryotes, transcription factors (TFs) and chromatin, but not yet how they function on a molecular level. This relates to the fact that, in contrast to many other basic building blocks of eukaryotic cells, TFs and chromatin are either not present in bacteria or have a very different protein structure (see figure 1). However, understanding these molecules on a biochemical basis, is essential for developing them as drug targets or utilizing them for bioengineering. The aim of my research group is thus to harness modern experimental techniques combined with computational analysis, to understand the biochemistry of TFs and chromatin.

Specific themes and goals

In my group we focus on three aspects of transcription factors (TFs) and chromatin and try to understand the biochemical basis for each of them:

  • Specificity: What determines the genes that TFs and chromatin regulate,
  • Dynamics: What are the timescales of the biochemical reactions and how do they connect to those of the physiological output
  • Interactions: how does the interaction between multiple “relatively simple” TFs and chromatin shape the complex regulatory networks we observe.

For this, we develop new molecular tools, like a molecular timer (1), and combine them with modern DNA synthesis methods and next-generation sequencing allowing us to conduct biochemical experiments with high-throughput and to investigate the protein side (TFs and chromatin) as well as the gene side. Experimentally, we approach these aspects from different complementary angles:

  • Classical sequence-function studies, e.g how does a certain part of a protein (TFs) enable its specificity,
  • Evolutionary, which sequence patterns are conserved during evolution and what do they do,
  • Bottom-up synthetic biology, can we generate new sequences with certain characteristics.

The first concrete projects in my lab will aim at answering the following questions:

  • What is the molecular code for eukaryotic Transcription factor specificity outside of the DNA binding domain and how did evolve?
  • What distinguishes the regulatory sequences of genes that are highly responsive to chromatin changes and TF binding and those that are robust?
Highlights and impact

During my PostDoc in the Barkai Lab (Weizmann Institute of Israel), I made several key contributions to the field of gene regulation in Eukaryotes that will serve as the basis for my own research group:

  • Optimized a high-throughput method for functional profiling of TFs, that enables the rapid characterization of dozens of DNA-binding proteins in-vivo and on a genome-wide scale (2, 3)
  • Applied engineering-principles and CRIPSR-Cas9 gene-editing for the systematic examination of TF sequence-function relationships(4, 5).
  • Developed a molecular timer for DNA binding proteins that allows to elucidate the dynamics of DNA binding proteins in-vivo and on a genome wide scale(1)
Group composition & projects/funding

My you research group is composed of two PhD students, Janine Sachs and Mohammed Shabi MK, as well as my Lab Manager Lennard Schmidt and BCCB undergraduate students that join our lab for their final year thesis.

Together we are currently working on a DFG-funded project on the evolution of TF binding specificity using the budding yeast as a model system.

Selected publications
  1. G. Yaakov, F. Jonas, N. Barkai, Measurement of histone replacement dynamics with genetically encoded exchange timers in yeast. Nat Biotechnol, (2021).
  2. T. Gera, F. Jonas, R. More, N. Barkai, Evolution of binding preferences among whole-genome duplicated transcription factors. Elife 11, (2022).
  3. D. K. Kumar et al., Complementary strategies for directing in vivo transcription factor binding through DNA binding domains and intrinsically disordered regions. Mol Cell 83, 1462-1473.e1465 (2023).
  4. B. Hurieva et al., Disordered sequences of transcription factors regulate genomic binding by integrating diverse sequence grammars and interaction types. Nucleic Acids Res, (2024).
  5. F. Jonas et al., The molecular grammar of protein disorder guiding genome-binding locations. Nucleic Acids Res 51, 4831-4844 (2023).