Project (Michael Lidschreiber - Kristina Zumer)
Genome transcription and regulation



We are uncovering the molecular mechanisms and systemic principles of genome transcription and regulation using a combination of structural biology with functional genomics and bioinformatics in human cells. We offer several projects that will explore regulation of transcription on a genome-wide scale with diverse sequencing approaches.

We have developed the experimental and computational tools for transient transcriptome sequencing, or TT-seq, a method that enables measuring of RNA synthesis rates (1) and mapping of enhancer landscapes in a dynamic way in vivo (1, 2). We have used TT-seq to follow cell differentiation events and cellular responses to hormones and other signals (3, 4), and to study transcriptional misregulation in cancer cells (5). Combining these data with other genome-wide data sets for "multi-omics" approaches, which integrated with theoretical modeling, enables us to extract additional kinetic parameters of transcription. We can estimate several essential mechanisms of transcriptional regulation in human cells. Specifically, how long RNA polymerase II pauses at the beginning of genes (6, 7); what is the RNA polymerase II elongation velocity across entire genes (8) and how pre-mRNA splicing and transcription are coupled (9). Additionally, we utilize CRISPR/Cas9 to engineer cells in which we can rapidly and specifically degrade or inhibit proteins regulating transcription.

We continue to develop and use functional genomics methods and computational approaches to study the mechanisms of enhancer function, differentiation, and RNA metabolism, including transcription-coupled RNA processing. Work on these projects requires experimentalists (life sciences background) and computational biologists (background in mathematics, informatics etc.) with a strong interest in dissecting molecular mechanisms of transcription and its regulation. Possible projects will be developed together with candidates interested in specific areas.

In our research group we also offer PhD projects in structural biology and in vitro systems:
https://www.uni-goettingen.de/de/application/682457.html





Homepage Research Group
http://www.mpinat.mpg.de/cramer>



Publications:

(1) Schwalb B, Michel M, Zacher B, Frühauf K, Demel C, Tresch A, Gagneur J, Cramer P. TT-seq maps the human transient genome. Science. 2016 Jun 3; 352(6290):1225-8.

(2) Michel M, Demel C, Zacher B, Schwalb B, Krebs S, Blum H, Gagneur J, Cramer P. TT-seq captures enhancer landscapes immediately after T-cell stimulation. Molecular Systems Biology. 2017 Mar 7;13(3):920.

(3) Choi J, Lysakovskaia K, Stik G, Demel C, Söding J, Tian TV, Graf T, Cramer P. Evidence for additive and synergistic action of mammalian enhancers during cell fate determination. eLife. 2021 10, e65381.

(4) Sawicka A, Villamil G, Lidschreiber M, Darzacq X, Dugast‐Darzacq C, Schwalb B, Cramer P. Transcription activation depends on the length of the RNA polymerase II C‐terminal domain. EMBO Journal. 2021 40 (9), e107015.

(5) Lidschreiber K, Jung LA, von der Emde H, Dave K, Taipale J, Cramer P, Lidschreiber M. Transcriptionally active enhancers in human cancer cells. Molecular Systems Biology. 2021 17 (1), e9873.

(6) Gressel S, Schwalb B, Cramer P. The pause-initiation limit restricts transcription activation in human cells. Nature Communications. 2019 10 (1), 3603.

(7) Gressel S, Schwalb B, Decker TM, Qin W, Leonhardt H, Eick D, Cramer P. CDK9-dependent RNA polymerase II pausing controls transcription initiation. eLife. 2017 6, e29736.

(8) Zumer K, Maier KC, Farnung L, Jaeger MG, Rus P, Winter G, Cramer P. Two distinct mechanisms of RNA polymerase II elongation stimulation in vivo. Molecular Cell. 2021 81 (15), pp. 3096 - 3109.e8.

(9) Caizzi L, Monteiro-Martins S, Schwalb B, Lysakovskaya K, Schmitzova J, Sawicka A, Chen Y, Lidschreiber M, Cramer P. Efficient RNA polymerase II pause release requires U2 snRNP function. Molecular Cell. 2021 May 6;81(9