Role of epigenetic regulators in embryonic development

During embryonic development, proliferating cells become restricted in their fate through the combined action of cell type-specific transcription factors and ubiquitous epigenetic machinery. The molecular functions of these regulators are generally well understood, but assigning direct developmental roles to them is limited by complex mutant phenotypes that often emerge after gastrulation. In collaboration with the Smith lab at Yale Medical School, we use advanced strategies like combined zygotic perturbation and single-cell RNA-sequencing to simultaneously assay many mutant mouse embryos and analyze their morphological and transcriptional information to understand their precise roles across time and space.

Grosswendt, S.; Kretzmer, H.; Smith, Z. D.; Sampath Kumar, A.; Hetzel, S.; Wittler, L.; Klages, S.; Timmermann, B.; Mukherji, S.; Meissner, A.: Epigenetic regulator function through mouse gastrulation. Nature 584, pp. 102 - 108 (2020)
Haggerty, C.; Kretzmer, H.; Riemenschneider, C.; Sampath Kumar, A.; Mattei, A. L.; Bailly, N.; Gottfreund, J.; Giesselmann, P.; Weigert, R.; Brändl, B. et al.; Giehr, P.; Buschow, R.; Galonska, C.; von Meyenn, F.; Pappalardi, M. B.; McCabe, M. T.; Wittler, L.; Giesecke-Thiel, C.; Mielke, T.; Meierhofer, D.; Timmermann, B.; Müller, F.-J.; Walter, J.; Meissner, A.: Dnmt1 has de novo activity targeted to transposable elements. Nature Structural and Molecular Biology 28 (7), pp. 594 - 603 (2021)

Cancer epigenetics

We seek to understand the role of the epigenome in cancer development. Almost all cancer types are marked by a globel shift in DNA methylation, resulting in hypermethylation of select promoters and a global decrease. Are these changes merely a cause or a consequence of the malignant transformation or maybe even a prerequisite? By applying the latest sequencing technologies, like dual single-cell DNA methylation and RNAseq, we aim to dissect basic molecular mechanisms, including the role of DNA methylation and other epigenetic modifications distinguishing cancer from its benign counterparts.

Kretzmer H*, Bernhart SH*, Wang W*, Haake A*, Weniger MA*, Bergmann AK*, …, Lichter P, Siebert R,  Hoffmann S, Radlwimmer S.
DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control. 
Nature Genetics (2015)
Kretzmer, H.; Biran, A.; Purroy, N.; Lemvigh, C. K.; Clement, K.; Gruber, M.; Gu, H.; Rassenti, L.; Mohammad, A. W.; Lesnick, C. et al.; Slager, S. L.; Braggio, E.; Shanafelt, T. D.; Kay, N. E.; Fernandes, S. M.; Brown, J. R.; Wang, L.; Li, S.; Livak, K. J.; Neuberg, D. S.; Klages, S.; Timmermann, B.; Kipps, T. J.; Campo, E.; Gnirke, A.; Wu, C. J.; Meissner, A.: Pre-neoplastic alterations define CLL DNA methylome and persist through disease progression and therapy. Blood Cancer Discovery 2 (1), pp. 54 - 69 (2021)

Tumor classification

In collaboration with Franz-Josef Müller from the University Hospital Schleswig-Holstein and his group at the Max Planck Institute, we are developing a combination of wet-lab and computational approaches to sequence and to classify tumor samples based on its genetic and epigenetic markers in real-time. To make this possible, we use Nanopore sequencing with library preparation times below an hour and directly evaluate the sequencing data for tumor class prediction as they come off the sequencer.

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