Research Groups

Transposon silencing & heterochromatin formation by small RNAs

There is an ongoing arms race between eukaryotic genomes and transposable elements. The Brennecke lab studies the biology and mechanism of an RNA interference system that silences transposons in animal gonads—the piRNA pathway. piRNA-mediated repression of transposons is crucial for fertility and thus species survival. Research into this genome surveillance pathway has produced remarkable discoveries in various fields – such as small RNA biology, gene silencing, heterochromatin formation, epigenetics, and gametogenesis. We combine genetics, genomics, and biochemical approaches to uncover the molecular principles that underlie key features of the piRNA pathway: its enormous potency and specificity in silencing, and its ability to constantly adapt to challenges posed by new and evolving transposons.
 

Keywords: transposons, piRNAs, heterochromatin, epigenetics, small RNAs

Functional Genomics in Embryonic Stem Cells   

Embryonic stem cells represent the immortal in vitro capture of a very early stage of mammalian development. They maintain the potential to give rise to all cell types of the body and therefore carry the promise to transform our understanding of development and treatment of disease. The Elling lab studies embryonic stem cell biology using forward genetic screens by employing and optimizing state-of-the-art screening technologies such as haploid genetics and CRISPR/Cas9. We probe stem cell biology and ask questions about lineage maintenance, lineage transition, and the underlying epigenetic programs.     

Keywords: haploid, screen, CRISPR/Cas, embryonic stem cell, cell fate

THEORETICAL MODELS OF CHROMOSOME STRUCTURE

Each human cell contains a staggering amount of DNA – billions of molecular basepairs that would stretch up to 6 meters in length if placed end-to-end! Imagine a cell magnified 100,000 times – it would have a nucleus one meter in diameter containing genomic DNA in 300 spools of thin fishing line – 3000km long and 0.2 mm in diameter. Not only do cells have to access the tightly packed DNA for transcription to RNA, genomes must be accurately duplicated, disentangled and passed along to daughter cells, all while maintaining them intact. To perform these basic functions reliably in a variety of organisms and conditions, evolution has come up with complex machinery and creative mechanisms, some of which we study in our lab using computational – or dry – research methods based in statistical physics and computational biology. 

Keywords: biophysics, polymer models, computational biology, chromosomes, mitosis, DNA repair, gene regulation

Brain development and disease

The human brain is the most complex of all organs. In the Knoblich lab, we are fascinated by the mechanisms behind its assembly and function, and study them using a unique combination of model organisms ranging from insects to humans. So far, analysis of the simple nervous system of the fruit fly, Drosophila melanogaster, has allowed us to understand how neural stem cells divide and differentiate to generate diverse neurons, as well as how defects in these processes can cause tumor formation. To analyze these events directly in human brain tissue, we have recently developed the cerebral organoid system that generates human fetal brain-like tissue from pluripotent stem cells in vitro. This system allows us, in collaboration with clinical research groups, to derive three-dimensional culture models for neuro-psychiatric disorders and analyze their developmental origin in a deeply mechanistic manner. Our analysis of brain development will illuminate the causes behind, and potential therapies for various neurodevelopmental and neurological disorders.

Keywords: stem cell, brain, organoids, neurogenesis, neurons

Molecular control of human Cardiogenesis

The heart is the first organ that forms in humans but how molecules instruct cells to form such a fascinating structure is not understood. The aim of the Mendjan lab is to recapitulate human heart development in vitro, discover the molecular mechanisms that drive cardiac self-organization, and how this fails in congenital heart disease. Our approach is to use human pluripotent stem cell differentiation into self-organizing heart organoids called "cardioids" to decipher the molecular control of cardiac organogenesis, and of associated disorders. 

Keywords: Heart development, human pluripotent stem cells, self-organization, cardiac organoids, cardioids

Synthetic development

Throughout evolution, embryos developed efficient ways of emanating from stem cells. The Rivron lab recreates embryonic development using stem cells in a dish to better understand the encoded principles of self-organization. We use blastocysts and self-organizing models formed from stem cells, that we termed blastoids, to investigate how and why the flow of information between cells regulates spatio-temporal patterning and cell-fate decision making. This requires to consider blastocysts as complex systems from the viewpoint of physicists and engineers. We are a team of stem cell biologists, geneticists, synthetic biologists and engineers whose research is grounded in technological and computational approaches (e.g., microsystems, single cell sequencing, three-dimensional high content imaging) and collaborating with physicists.

Keywords: blastoids, stem cells, self-organisation

Regulation of Neural Stem Cell Quiescence

Adult neural stem cells (NSCs) generate neurons throughout life which integrate into existing circuits modulating memory and behavior. A key feature of adult NSCs is that most are in an inactive state (quiescence) until receiving activation stimuli. Since adult NSCs have a limited ability to self-renew, their activation is coupled with exhaustion, explaining the decline in neurogenesis with age. We investigate the mechanisms driving the transition of adult NSCs between proliferation and quiescence to devise strategies to prevent their exhaustion. We use in vivo and in vitro tools to understand how extrinsic signals, like diet and Insulin/IGF signaling, regulate adult NSC behavior.

Keywords: brain, adult stem cells, quiescence, niche, metabolism, signaling

CHROMATIN REPROGRAMMING IN TOTIPOTENT EMBRYOS

Within a matter of hours, fertilization transforms highly differentiated cells - gametes -  into a single totipotent cell with the potential to give rise to a complete organism. Gametes like egg and sperm are generated by meiosis. Meiotic chromosome segregation in eggs becomes more error-prone in females as they age, leading to trisomic pregnancies and aberrant embryonic development. The Tachibana lab studies both the causes of age-related chromosome missegregation in eggs and the natural reprogramming that occurs after fertilization to produce a totipotent embryo. How chromatin loses the epigenetic memory of a differentiated gamete state and is reprogrammed to a state of totipotency remains poorly understood. We use mechanistic cell biology, 3D spatial chromatin organization, 4D live-cell imaging and mouse molecular genetics to investigate how chromatin is reprogrammed in totipotent embryos. Our goals are to uncover the mechanisms that underlie the oocyte maternal-age-effect and zygotic reprogramming, which could illuminate new therapeutic strategies for reproductive and regenerative medicine.   

Keywords: totipotency, stem cells, chromatin organization, epigenetic reprogramming, zygotes, oocytes