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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 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 from a distance to activate their target gene remains enigmatic. Many genes are regulated by multiple enhancers, and their interplay is poorly understood. We will resolve how enhancers communicate with their target promoters by combining genome wide approaches with targeted genome engineering and a novel synthetic locus to study enhancer cooperativity.
We study how enhancers regulate their target gene in a highly controlled environment: We developed a synthetic gene locus that allows for the integration of individual and combinations of enhancers into a neutral environment. A single fluorescent reporter gene allows for a fast and highly reproducible readout of enhancer activity. Through the combination of massively parallel reporter assays (MPRAs), imaging of transcriptional bursting events and 3D genome mapping, we will gain deep mechanistic insights into enhancer function from a distance. Furthermore, we use the exit from naive pluripotency as an ideal model system to analyze changes in the enhancer activity during differentiation.
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.
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By definition, enhancers can activate a promoter from a distance, but with increasing distance, the ability to activate decreases. To systematically study how distance between enhancer and promoter affects transcription, we have developed a novel synthetic tool that allows for the integration of indvidual and combinations of enhancer elements into a neutral genomic locus. With this tool we demonstrate that while activation decreases with distance, the incoporation of additional, weak elements can increase the active radius of an enhancer. 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.
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.
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.
Christa Buecker
Group Leader +43 1 4277 74646
Room: 3.626
Tamara Civetta
PhD Student +43 1 4277 74647
Songjie Feng
PhD Student +43 1 4277 74647
Room: 3.510
María García Gallardo
PhD Student +43 1 4277 74647
Room: 3.510
Florian Halhammer
PhD Student +43 1 4277 74647
Room: 3.510
Felix Haslhofer
PhD Student +43 1 4277 74647
Room: 3.510
Marie Huber
Lab Manager +43 1 4277 74647
Room: 3.510
Mattias Jonasson
PhD Student +43 1 4277 74647
Room: 3.510
Isabella Völkl
PhD Student +43 1 4277 74647
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 Principal Investigator grant reviewed and funded by the Austrian Research Fund FWF to explore to interaction and redundancies among enhancers in naive pluripotency and during the establishment of formative pluripotency.
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 Buecker lab was awarded an ERC CoG 2024 for their project GENE-TUNE to build gene regulatory landscapes from the bottom up to understand enhancer-promoter communication.
The Group Buecker is a member of the special Doctoral Program "Signaling Mechanisms in Cellular Homeostasis" reviewed and funded by the Austrian Research Fund FWF.
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)
Now: Postdoc with Timothy Lionnet (NYU)
Now: Postdoc with Wayne Stallaert (University of Pittsburgh)