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During development, cells undergo numerous tightly regulated differentiation steps that are each characterized by distinct changes in gene expression to ultimately generate all the different cell types in the human body. The correct temporal and spatial gene expression patterns in these cell fate transitions are controlled by enhancers: short DNA sequences that regulate the expression of their target gene from a distance. Changes in the enhancer landscape have been mapped in numerous cell states, but how enhancers function to activate their target gene remains enigmatic. Furthermore, within a population of cells, each single cell initiates differentiation at a distinct time point. What leads to the initiation of differentiation and how do single cells transition from one cell state into the next, closely related one? Our lab wants to understand how these transcriptional changes driven by enhancers are orchestrated on the single cell level.
We study how enhancers are activated and regulate their target gene in a highly controlled developmental system: The exit from naïve pluripotency. In this differentiation, mouse embryonic stem cells transition into a transient cell state resembling the late post-implantation epiblast. Though combination of next generation sequencing based approaches both on population and on single cells, imaging to follow transcriptional changes using reporters, and CRIPSRP-Cas9 based genome wide screening methods we will dissect this cell fate transition in detail. Through focusing on one cell fate transition we will gain deep mechanistic insights into cellular decision making that will inform regenerative medicine approaches in the future.
Christa Buecker studied Biology at the University Stuttgart. She joined Niels Geijsen's lab at MGH and Harvard Stem Cell Institute in Boston, USA to study human pluripotency. For her postdoctoral work, she moved to Stanford to study transcriptional changes and enhancers in early embryonic development in Joanna Wysocka's lab. In 2015, she started her own group at Max Perutz Labs.
Epigenomic mapping has led to the identification of numerous putative enhancer elements within one cell state and often multiple enhancers can be found in the vicinity of one putative target gene. But how are these enhancer elements working together? We have dissected the enhancer elements that control the expression of Fgf5 during the exit from naive pluripotency. Surprisingly, individual elements had low intrinsic enhancer activity, however, multiple elements work together in a super-additive manner to activate the target gene at the endogenous locus. See our publication in Molecular Cell.
Stem cells express a set of genes that are normally upregulated in the event of infection. However, in stem cells, these interferon stimulated genes are not triggered through an external event, their regulation was so far unclear. During the exit from naive pluripotency, the same transcription factors that are driving the differentiation, are also responsible for the upregulating Irf1, a master transcription factor that protects cells from viral infection. See our publication in EMBO Reports.
Genome wide changes in the enhancer landscape during the exit from naïve pluripotency are driving by reorganization of the pluripotency master regulator Oct4 to newly activated enhancers through collaboration with Otx2. This work highlights the combinatorial nature of transcriptional regulation and builds the foundation to understand this cell fate transition in depths. See our publication in Cell Stem Cell.
Transient upregulation of IRF1 during exit from naive pluripotency confers viral protection.
Romeike, Merrit; Spach, Stephanie; Huber, Marie; Feng, Songjie; Vainorius, Gintautas; Elling, Ulrich; Versteeg, Gjis A; Buecker, Christa
Temporal dissection of an enhancer cluster reveals distinct temporal and functional contributions of individual elements.
Thomas, Henry F; Kotova, Elena; Jayaram, Swathi; Pilz, Axel; Romeike, Merrit; Lackner, Andreas; Penz, Thomas; Bock, Christoph; Leeb, Martin; Halbritter, Florian; Wysocka, Joanna; Buecker, Christa
Reorganization of enhancer patterns in transition from naive to primed pluripotency.
Buecker, Christa; Srinivasan, Rajini; Wu, Zhixiang; Calo, Eliezer; Acampora, Dario; Faial, Tiago; Simeone, Antonio; Tan, Minjia; Swigut, Tomasz; Wysocka, Joanna
Enhancers as information integration hubs in development: lessons from genomics.
Buecker, Christa; Wysocka, Joanna
A murine ESC-like state facilitates transgenesis and homologous recombination in human pluripotent stem cells.
Buecker, Christa; Chen, Hsu-Hsin; Polo, Jose Maria; Daheron, Laurence; Bu, Lei; Barakat, Tahsin Stefan; Okwieka, Patricia; Porter, Andrew; Gribnau, Joost; Hochedlinger, Konrad; Geijsen, Niels
The Buecker is funded through a standalone grant reviewed and funded by the Austrian Research Fund FWF to explore to interaction and redundancies among transcription factors in the establishment of formative pluripotency.
The Group Buecker is a member of the special doc.funds Program "Stem Cells, Tissues, Organoids – Dissecting Regulators of Potency and Pattern Formation" reviewed and funded by the Austrian Research Fund FWF.
Now: Postdoc with Ludovic Vallier (Berlin Institute of Health at Charite Berlin)