RG Ibrahim: Gene Regulation in Cell Differentiation and Disease

The precise control of gene expression underlies all cell differentiation during an organisms life. Gene misexpression can be the cause of congenital as well as acquired disease. In recent years, we have focused on how the folding of 3D chromatin structure inside the nucleus affects gene regulation and how mutations reorganize 3D chromatin structure and thereby cause gene misexpression and disease. However, we also study how mutations in transcription factors alter gene regulation and ultimately cause disease.

We aim to understand the genetic principles of gene regulation and how they are connected to cell differentiation and disease. For this we combine genome engineering in mouse embryonic stem cells with cell differentiation systems and cutting-edge genomic analyses.

Our research focuses on the regulation of key genes in vertebrate heart development as well as the identifying causative genetic variants underlying early onset osteoporosis. For this we map the important gene regulatory elements in osteoclasts and osteoblasts, two cell types controlling in bone development and homeostasis.

Research focus

  • linking 3D chromatin structure to gene regulation and disease
  • development of complex and/or high-throughput genome engineering to create genetic models of disease
  • gene regulatory control of vertebrate heart development and cardiac cell differentiation
  • Defining the active regulatory genome in osteoblasts and osteoclasts
  • Genetic variant interpretation of heredetary osteoporosis

Publications  

Key publications that address our study of how mutations affecting the 3D chromatin structure cause gene misexpression and disease.

  • Basu, S.*,  S.D. Mackowiak*, H. Niskanen, D. Knezevic, V. Asimi, S. Grosswendt, H. Geertsema, S. Ali, Salaheddine, I. Jerković, H. Ewers, S. Mundlos, A. Meissner, D. M. Ibrahim and D. Hnisz "Unblending of Transcriptional Condensates in Human Repeat Expansion Disease". Cell doi:10.1016/j.cell.2020.04.018 (2020)
  • Ibrahim, D.M., & Mundlos, S. "The role of 3D chromatin domains in gene regulation: a multi-facetted view on genome organization"Curr Opin Genet Dev, 61, 1–8, doi:10.1016/j.gde.2020.02.015 (2020)
  • Ibrahim, D. M. & Mundlos, S. "Three-dimensional chromatin in disease: What holds us together and what drives us apart?"Curr Opin Cell Biol 64, 1-9, doi:10.1016/j.ceb.2020.01.003 (2020)
  • Despang, A., R. Schopflin, M. Franke, S. Ali, I. Jerkovic, C. Paliou, W. L. Chan, B. Timmermann, L. Wittler, M. Vingron, S. Mundlos* and D M. Ibrahim*  "Functional dissection of the Sox9-Kcnj2 locus identifies nonessential and instructive roles of TAD architecture". Nat Genet 51, 1263-1271, doi:10.1038/s41588-019-0466-z (2019).
  • Cao, J.*, M. Spielmann*, X. Qiu, X. Huang, D.M. Ibrahim, A. J. Hill, F. Zhang, S. Mundlos, L. Christiansen, F. J. Steemers, C. Trapnell and J. Shendure "The single-cell transcriptional landscape of mammalian organogenesis". Nature 566, 496–502 (2019). doi:10.1038/s41586-019-0969-x
  • Kraft, K.*, A. Magg*, V. Heinrich*, C. Riemenschneider, R. Schopflin, J. Markowski, D.M. Ibrahim, R. Acuna-Hidalgo, A. Despang, G. Andrey, L. Wittler, B. Timmermann, M. Vingron and S. Mundlos "Serial genomic inversions induce tissue-specific architectural stripes, gene misexpression and congenital malformations". Nat Cell Biol 21, 305-310, doi:10.1038/s41556-019-0273-x (2019).
  • Franke, M.*, D.M. Ibrahim*, G. Andrey, W. Schwarzer, V. Heinrich, R. Schopflin, K. Kraft, R. Kempfer, I. Jerkovic, W. L. Chan, M. Spielmann, B. Timmermann, L. Wittler, I. Kurth, P. Cambiaso, O. Zuffardi, G. Houge, L. Lambie, F. Brancati, A. Pombo, M. Vingron, F. Spitz and S. Mundlos "Formation of new chromatin domains determines pathogenicity of genomic duplications". Nature 538, 265-269, doi:10.1038/nature19800 (2016).

Funding

DFG-Schwerpunktprogramm 2202: 

spp2202.charite.de

 

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