Professional Education


  • Doctor of Philosophy, Technische Universitat Berlin (2017)
  • Diplom, Technische Universitat Berlin (2011)

All Publications


  • Serial genomic inversions induce tissue-specific architectural stripes, gene misexpression and congenital malformations. Nature cell biology Kraft, K., Magg, A., Heinrich, V., Riemenschneider, C., Schopflin, R., Markowski, J., Ibrahim, D. M., Acuna-Hidalgo, R., Despang, A., Andrey, G., Wittler, L., Timmermann, B., Vingron, M., Mundlos, S. 2019

    Abstract

    Balanced chromosomal rearrangements such as inversions and translocations can cause congenital disease or cancer by inappropriately rewiring promoter-enhancer contacts1,2. To study the potentially pathogenic consequences of balanced chromosomal rearrangements, we generated a series of genomic inversions by placing an active limb enhancer cluster from the Epha4 regulatory domain at different positions within a neighbouring gene-dense region and investigated their effects on gene regulation in vivo in mice. Expression studies and high-throughput chromosome conformation capture from embryonic limb buds showed that the enhancer cluster activated several genes downstream that are located within asymmetric regions of contact, the so-called architectural stripes3. The ectopic activation of genes led to a limb phenotype that could be rescued by deleting the CCCTC-binding factor (CTCF) anchor of the stripe. Architectural stripes appear to be driven by enhancer activity, because they do not form in mouse embryonic stem cells. Furthermore, we show that architectural stripes are a frequent feature of developmental three-dimensional genome architecture often associated with active enhancers. Therefore, balanced chromosomal rearrangements can induce ectopic gene expression and the formation of asymmetric chromatin contact patterns that are dependent on CTCF anchors and enhancer activity.

    View details for PubMedID 30742094

  • Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions CELL Lupianez, D. G., Kraft, K., Heinrich, V., Krawitz, P., Brancati, F., Klopocki, E., Hom, D., Kayserili, H., Opitz, J. M., Laxova, R., Santos-Simarro, F., Gilbert-Dussardier, B., Wittler, L., Borschiwer, M., Haas, S. A., Osterwalder, M., Franke, M., Timmermann, B., Hecht, J., Spielmann, M., Visel, A., Mundlos, S. 2015; 161 (5): 1012–25

    Abstract

    Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.

    View details for DOI 10.1016/j.cell.2015.04.004

    View details for Web of Science ID 000355152600010

    View details for PubMedID 25959774

    View details for PubMedCentralID PMC4791538

  • Deletions, Inversions, Duplications: Engineering of Structural Variants using CRISPR/Cas in Mice CELL REPORTS Kraft, K., Geuer, S., Will, A. J., Chan, W., Paliou, C., Borschiwer, M., Harabula, I., Wittler, L., Franke, M., Ibrahim, D. M., Kragesteen, B. K., Spielmann, M., Mundlos, S., Lupianez, D. G., Andrey, G. 2015; 10 (5): 833–39

    Abstract

    Structural variations (SVs) contribute to the variability of our genome and are often associated with disease. Their study in model systems was hampered until now by labor-intensive genetic targeting procedures and multiple mouse crossing steps. Here we present the use of CRISPR/Cas for the fast (10 weeks) and efficient generation of SVs in mice. We specifically produced deletions, inversions, and also duplications at six different genomic loci ranging from 1.1 kb to 1.6 Mb with efficiencies up to 42%. After PCR-based selection, clones were successfully used to create mice via aggregation. To test the practicability of the method, we reproduced a human 500 kb disease-associated deletion and were able to recapitulate the human phenotype in mice. Furthermore, we evaluated the regulatory potential of a large genomic interval by deleting a 1.5 Mb fragment. The method presented permits rapid in vivo modeling of genomic rearrangements.

    View details for DOI 10.1016/j.celrep.2015.01.016

    View details for Web of Science ID 000349404400017

    View details for PubMedID 25660031

  • ONCOGENIC 3D TUMOR GENOME ORGANIZATION IDENTIFIES NEW THERAPEUTIC TARGETS IN EPENDYMOMA Okonechnikov, K., Huebner, J., Chapman, O., Chakraborty, A., Pagadala, M., Bump, R., Chandran, S., Kraft, K., Hidalgo, R., Mundlos, S., Wechsler-Reya, R., Juarez, E. F., Coufal, N., Levy, M., Crawford, J., Pajtler, K., Reid, D., Schmitt, A., Carter, H., Ay, F., Dixon, J., Mesirov, J., Pfister, S. M., Kool, M., Chavez, L. OXFORD UNIV PRESS INC. 2020: 308
  • TARGETING OF EPENDYMOMA AS INFORMED BY ONCOGENIC 3D GENOME ORGANIZATION Okonechnikov, K., Hubner, J., Chapman, O., Chakraborty, A., Bump, R., Chandran, S., Kraft, K., Hidalgo, R., Mundlos, S., Coufal, N., Levy, M., Crawford, J., Ay, F., Mesirov, J., Pajtler, K., Dixon, J., Pfister, S., Kool, M., Chavez, L. OXFORD UNIV PRESS INC. 2019: 100
  • CHROMOSOME CONFORMATION ANALYSIS OF EPENDYMOMA IDENTIFIES PUTATIVE TUMOR DEPENDENCY GENES ACTIVATED BY DISTAL ONCOGENIC ENHANCERS Okonechnikov, K., Huebner, J., Kraft, K., Hidalgo, R., Bump, R., Chandran, S., Mundlos, S., Mesirov, J., Pajtler, K., Dixon, J., Pfister, S., Kool, M., Chavez, L. OXFORD UNIV PRESS INC. 2019: 80–81
  • Serial genomic inversions induce tissue-specific architectural stripes, gene misexpression and congenital malformations NATURE CELL BIOLOGY Kraft, K., Magg, A., Heinrich, V., Riemenschneider, C., Schoeflin, R., Markowski, J., Ibrahim, D. M., Acuna-Hidalgo, R., Despang, A., Andrey, G., Wittler, L., Timmermann, B., Vingron, M., Mundlos, S. 2019; 21 (3): 305-+