Prof. Ingrid LohmannDevelopmental Biology
Current research in my lab is based on an integrated approach of advanced genomic, genetic, molecular, and biochemical methods together with extensive computational analysis and simulation to determine on the one hand how Hox proteins orchestrate different aspects of development, with a special focus on stem cell maintenance in the testis and nervous system development and morphogenesis, and, on the other hand, how they achieve the spatio-temporally restricted expression of their target genes in specific cell and tissue types. In addition, we have also started to identify and study processes involved in cancer formation and progression.
Recent research highlights
Single-cell RNA sequencing of motoneurons identifies regulators of synaptic wiring in Drosophila embryos
Multi-level and lineage-specific interactomes of the Hox transcription factor Ubx contribute to its functional specificity
Transcriptional Control of Development by Hox Proteins
One of the paradigm-shifting breakthroughs in biology was the discovery that the molecular mechanisms underlying many developmental pathways have been conserved during evolution even between distantly related species. This quantum-leap was triggered by the realisation that Hox genes, which were known to specify segment identities in flies, are also present in humans and worms.
Hox genes were originally discovered in Drosophila because of their drastic homeotic mutant phenotypes and are expressed in specific domains along the main Anterior/Posterior body axis. They code for transcription factors, which assign specific morphologies to individual segments by regulating distinct sets of downstream genes. While the Hox proteins are active in thousands of cells throughout an animal’s life, many of their downstream genes are only expressed in specific subpopulations of cells. Thus, in order to understand Hox dependent cell behaviour during development and diversification of morphogenetic structures along the body axis, it is essential to identify the function and the cell-type specific regulation of many of their downstream genes. However, until recently only a few Hox downstream genes and their corresponding Hox regulated enhancers were known. Consequently, the cellular mechanisms of Hox dependent morphogenesis are still only poorly understood.
Work in my own group has expanded into two major directions. On the one hand, we have begun to systematically identify Hox downstream genes on the whole-genome level with the idea to identify and study all aspects of Hox dependent regulatory networks. To this end we have performed a comparative transcriptome screen probing six of the eight Drosophila Hox genes, which resulted in the first comprehensive atlas of Hox downstream genes containing many hundreds of transcripts. Functional classification using Gene Ontology terms allowed us to link the Hox response to diverse developmental processes, for example nervous system diversification and stem cell maintenance / differentiation. Thus, for the first time since the discovery of Hox genes more than 20 years ago, these results now allow us to study these processes under the control of Hox genes on a quantitative and mechanistic level.
The second major goal of my lab is to understand how Hox proteins acquire spatio-temporal precision and cell-type specificity in regulating their target genes despite their broad expression. Hox proteins seem to solve this problem by interacting with different types of transcriptional partners to form large regulatory complexes thereby enabling Hox transcription factors to achieve their highly diverse and specific transcriptomic outputs. However, so far all attempts to characterize Hox complexes have been unsuccessful. This is very likely due to the highly dynamic regulatory activities of Hox transcription factors in space and time in the living animal, and thus cell-type and stage-specific in vivo approaches are required to elucidate Hox-cofactor and Hox-chromatin interactions critical for their spatio-temporal in vivo function.To this end, we have established the Isolation of Nuclei TAgged in specific Cell Types (INTACT) method, which we now use to dissect the cis-regulatory requirements for tissue- and stage-specific Hox function by identifying in the embryonic mesoderm and nervous system chromatin modifications, binding profiles (ChIPseq) and direct target genes (RNAseq) for different Hox proteinns. Furthermore, we have established the CRISPR/Cas system in the lab, which allows us to tag and modify Hox proteins, thereby allowing a cel type specific isolation of Hox regulatory in vivo complexes. In sum, my lab has developed new tools, which will greatly improve our understanding of the general mechanisms guiding temporal and spatial activity of TFs in vivo.
Velten, J., Gao, X., Van Nierop y Sanchez, P., Domsch, K., Agarwal, R., Bognar, L., Paulsen, M., Velten, L. and Lohmann, I. (2022). Single-cell RNA sequencing of motoneurons identifies regulators of synaptic wiring in Drosophila embryos. Mol Syst Biol 18:e10255. doi: 10.15252/msb.202110255.
Carnesecchi, J., Boumpas, P., Van Nierop y Sanchez, P., Domsch, K., Pinto, H.D., Pinto, P. and Lohmann, I. (2022). The Hox transcription factor Ubx binds RNA and regulates co-transcriptional splicing through an interplay with RNA polymerase II. Nucleic Acids Res 50:763-783. doi: 10.1038/s41467-021-23293-8.
Carnesecchi, J., Sigismondo, G., Domsch, K., Baader, C.E.P., Rafiee, M.R., Krijgsveld, J. and Lohmann, I. (2020). Multi-level and Lineage-specific Interactomes of the Hox Transcription Factor Ubx contribute to its Functional Specificity. Nat Comm 13;11(1):1388. doi: 10.1038/s41467-020-15223-x.
Domsch K, Carnesecchi J, Disela V, Friedrich J, Trost N, Ermakova O, Polychronidou M and Lohmann I (2019). The Hox Transcription Factor Ubx stabilizes Lineage Commitment by Suppressing Cellular Plasticity in Drosophila. eLife, pii: e42675. doi: 10.7554/eLife.42675.
Tamirisa, S., Papagiannouli, F., Rempel, E., Ermakova, O., Trost, N., Zhou, J., Mundorf, J., Brunel, S., Ruhland, N., Boutros, M., Lohmann, J. U., and Lohmann I. (2018). Decoding the regulatory logic of the Drosophila male stem cell system. Cell Rep 24, 3072-3086.
Friedrich J., Sorge S., Bujupi F., Eichenlaub M.P., Schulz N.G., Wittbrodt J. and Lohmann I. Direct and Cell type-specific Hox Function is required for the Development and Maintenance of the Drosophila Feeding Motor Unit. Cell Reports, 2016 Feb 2;14(4):850-860.
Papagiannouli F., Schardt L., Grajcarek J., Ha N. and Lohmann I. (2014) The Hox Gene Abd-B Controls Stem Cell Niche Function in the Drosophila Testis. Developmental Cell, Jan 27; 28 (2), 189-202.
Sorge S., Ha N., Polychronidou M., Friedrich J., Bezdan D., Kaspar P., Schaefer M.H., Ossowski S., Henz S.R., Mundorf J., Rätzer J., Papagiannouli F. and Lohmann I. (2012) The cis-regulatory code of Hox function in Drosophila. The EMBO Journal, Jul 10;31(15):3323-33.
Stöbe P., Stein, M. A. S., Habring-Müller, A., Bezdan, D., Fuchs, A. L., Hueber, S. D., Wu, H. and Lohmann I. (2009) Multifactorial regulation of a Hox target gene. PLoS Genet. 5(3): e1000412.
Hueber, S. D., Bezdan, D., Henz, S. R., Blank, M.,Wu, H. and Lohmann, I. (2007). Comparative analysis of Hox downstream genes in Drosophila. Development 134, 381-392.
Lohmann I., McGinnis, N., Bodmer, N. and McGinnis W. (2002). The Drosophila Hox gene Deformed sculpts head morphology via direct regulation of the apoptosis activator reaper. Cell 110, 457-466.