Patrick Cramer
Patrick Cramer
Phone:+49 551 201-2800

Curriculum Vitae

Janine Koschmieder
Janine Koschmieder
Phone:+49 551 201-2800Fax:+49 551 201-2803

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Movie: RNA Polymerase II transcription

Link to the Research Group Computational Biology (Dr. Johannes Soeding)

Link to our satellite lab at the Karolinska Institute in Stockholm, Sweden

<sup>Jürgen Howaldt, Wikimedia Commons-CC BY-SA 2.0 DE-Lizenz</sup>
Jürgen Howaldt, Wikimedia Commons-CC BY-SA 2.0 DE-Lizenz

Summary of research results

Patrick Cramer

Header image 1383320086

Department of Molecular Biology

Our mission

Understanding transcription of the genome and its regulation

Our approach

We are an interdisciplinary team of researchers who wish to understand how chromatin is transcribed and how transcription of our genome is regulated in health and disease. We combine structural biology with functional genomics and bioinformatics to unravel the intricate transcription processes in eukaryotic cells. Our aim is to define the molecular mechanisms underlying chromatin transcription and genome regulation.

Why it is important

Transcription is the first step in the expression of our genetic information and a focal point for gene regulation during cell differentiation, organism development, and throughout life. Unravelling the mechanisms of transcription and its regulation will enable us to understand how genes are switched on, and how genes are dysregulated in diseases such as cancer.

Structural biology reveals large complexes

To study mechanisms, we determine the three-dimensional structure of large transcription complexes. We integrate cutting-edge structural biology methods, in particular cryo-electron microscopy, X-ray crystallography, and crosslinking-mass spectrometry. The obtained structures are then combined with functional studies using biochemistry.

Current structural studies and methods development

Our structural studies led to the first molecular movie of transcription by RNA polymerase II, the enzyme that synthesis mRNA from protein-coding genes (Cheung and Cramer, Cell 2012). Recently, we provided insights into the mechanisms of transcription initiation by three different RNA polymerases from their promoters (Schilbach et al., Nature 2017; Engel et al. Cell 2017; Hillen et al., Cell 2017). We also provided the structure of the central coactivator complex core Mediator (Nozawa et al., Nature 2017), and the structure of a chromatin-remodelling factor bound to the nucleosome (Farnung et al., Nature 2017). Over the years, we have contributed to the development of techniques used to determine the structure of large molecular assemblies. In the future, we will study the structural basis for transcription regulation in chromatin and we will further develop structural biology methods.

The functional genome and RNA metabolism

We also develop and use functional genomics methods and computational approaches to unravel the mechanisms of genome regulation in living cells. With the help next-generation sequencing-based methods we monitor regulatory landscapes and RNA metabolism in cells. We further use multi-omics approaches to study mechanistic aspects of transcription in vivo.

Current genomics and bioinformatics studies

Recent advances now allow us to monitor transcription regulation of the human genome. We can monitor all transcription activity in cells by next-generation sequencing of newly synthesized RNA (TT-seq), localize transcriptionally engaged RNA polymerase II over the genome (NET-seq), map the bindings sites of regulatory proteins over the genome (ChIP-seq), and map the location of regulatory RNA-binding factors over the transcriptome (PAR-CLIP). By combining these techniques and evaluating the obtained systemic data with a computational biology approach we uncover principles of genome regulation. Recent achievements include our development of transient transcriptome sequencing, or TT-seq (Schwalb, Michel, Zacher et al., Science 2016), that can be used to monitor dynamic changes in enhancer landscapes (Michel et al., Molecular Systems Biology 2017). We also developed a multi-omics approach to extract kinetic parameters of RNA polymerase initiation frequency, pause duration, and elongation velocity (Gressel, Schwalb, et al. eLife 2017). In the future we will monitor changes in regulatory landscapes during human cell activation and differentiation, and aim to define the rate-limiting steps underlying genomic regulation and RNA metabolism, including transcription-coupled RNA processing. We also develop methods to improve transcriptomics on the single cell and single molecule level.

<p class="Normal">Cryo-EM structure of the RNA polymerase II transcription pre-initiation complex with core Mediator</p>
<p class="Normal">© Schilbach et al. Nature 2017</p> Zoom Image

Cryo-EM structure of the RNA polymerase II transcription pre-initiation complex with core Mediator

© Schilbach et al. Nature 2017

<p class="Normal">Multi-omics approach extracts kinetic parameters of transcription, system-wide</p>
<p class="Normal">© Gressel, Schwalb et al., eLife 2017</p> Zoom Image

Multi-omics approach extracts kinetic parameters of transcription, system-wide

© Gressel, Schwalb et al., eLife 2017

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