Junior Research Group Mechanisms of Genome Control

Dr. Angelika Feldmann

© dkfz.de

The Feldmann lab studies how genes are regulated in time and space, and how these programs become corrupted in cancers. One of the most fascinating processes in biology is the development of a multicellular organism with >200 different cell types from just one single cell. This means that most of these cell types have exactly the same genetic content despite being highly diverse in their appearance and function. Such diversity is only possible if genes are precisely regulated in space and time. To achieve this, gene promoters must integrate inputs from distal gene regulatory elements (DREs), such as enhancers. Despite extensive studies, we still lack a general understanding about the mechanisms behind DRE-driven gene activation. Often located hundreds of kilobases away, DREs are thought to come into close physical proximity to their target genes, which involves folding of the DNA and is regulated by a number of proteins (Schoenfelder et al., 2019, Feldmann et al., 2020, Rhodes et al., 2020). Such physical interactions correlate with gene activity and are frequently altered in cancer, suggesting that they may be required for transcriptional alterations observed in normal development and carcinogenesis. Recent data, however, reveal that physical contacts between DREs and gene promoters can occur independently of gene activity (Ghavi-Helm et al., 2014; Benabdallah et al., 2019, Feldmann et al., 2020), indicating that other mechanisms underlie their function in gene activation.

Our mission is to understand the precise mechanisms by which DREs communicate with gene promoters during activation and maintenance of transcription, with a specific focus on the role of the 3D genome structure in this process. We combine state-of-the-art genomic, proteomic and computational biology approaches with high-throughput genetic engineering to dissect gene regulatory mechanisms in health and disease. We use embryonic stem cell differentiation and cancer cell lines, which are ideally suitable for genetic manipulation, as models for gene activation.

Contact

Dr. Angelika Feldmann
Mechanisms of Genome Control (B460)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 581
69120 Heidelberg
Tel: +49 6221 423474

Selected Publications

  • Feldmann, A.#, E. Dimitrova, A. Kenney, A. Lastuvkova and R. J. Klose# (2020). CDK-Mediator and FBXL19 prime developmental genes for activation by promoting atypical regulatory interactions. Nucleic Acids Res 48(6): 2942-2955.
  • Rhodes, J. D. P.*, A. Feldmann*, B. Hernandez-Rodriguez*, N. Diaz*, J. M. Brown, N. A. Fursova, N. P. Blackledge, P. Prathapan, P. Dobrinic, M. K. Huseyin, A. Szczurek, K. Kruse, K. A. Nasmyth, V. J. Buckle, J. M. Vaquerizas# and R. J. Klose# (2020). Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells. Cell Rep 30(3): 820-835 e810.
  • Dimitrova, E., T. Kondo*, A. Feldmann*, M. Nakayama, Y. Koseki, R. Konietzny, B. M. Kessler, H. Koseki and R. J. Klose# (2018). FBXL19 recruits CDK-Mediator to CpG islands of developmental genes priming them for activation during lineage commitment. Elife 7.
  • Ginno, P. A.*, D. Gaidatzis*, A. Feldmann*, L. Hoerner, D. Imanci, L. Burger, F. Zilbermann, A. Peters, F. Edenhofer, S. A. Smallwood, A. R. Krebs and D. Schubeler# (2020). A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity. Nat Commun 11(1): 2680.
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