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The Stadtfeld laboratory

During initial tissue formation and later homeostasis, mammalian cells constantly remodel chromatin to allow transcriptional changes needed for adaptation to developmental cues and environmental signals. The need for epigenetic and transcriptional flexibility has to be balanced with the requirement to maintain essential chromatin features in specific genomic regions. Failure to do maintain this balance can result in pathological chromatin alterations and cell death or worse, tissue malfunction and ultimately disease. Ex vivo culture of cells, a prerequisite for many biomedical and basic research applications, significantly exacerbates the risk to introduce pathological chromatin features. This poses a serious challenge for basic and biomedical research. The potential and the risk of epigenetic flexibility are particularly evident in the case of pluripotent stem cells, which can give rise to any cell type of the adult body but also are exceptionally prone to acquire detrimental epigenetic abnormalities.

What are the molecular mechanisms involved in the maintenance of epigenetic integrity in mammalian stem cells? How can they become derailed in disease and other pathological conditions? Our group explores different complementary approaches based on genetic engineering, epigenome profiling and mammalian genetics to understand how transcription factors and chromatin-modifying enzymes interact with each other and genomic features such as enhancers and other regulatory elements to control mammalian cell fate and epigenetic stability. We use mouse and human pluripotent stem cells, which we derive either from early stage embryos or via cellular reprogramming from adult somatic cells, as our main experimental model system. The long-term goal of our work is to facilitate the reliable and safe use of pluripotent stem cells in disease modeling and regenerative medicine.

From regulator to phenotype - studying the loss of epigenome regulators in stem cells


Prior work by us and others has identified important trans-acting regulator of epigenetic stability and cell fate identify, whose molecular function remains largely unknown. These include repressive histone modifying complexes essential to silence undesired transcriptional programs and transcriptional regulators necessary to establish or resolve the state of pluripotency. In different projects in the lab, we are exploring unique transgenic alleles we generate to reveal the molecular consequence of loss of these factors in mouse and human pluripotent cells and specific disease-relevant somatic cell types.

From phenotype to regulator - genetic determinants of epigenetic stability 

Genomic imprinting – the monoallelic expression of a subset of mammalian genes due to chromatin marks established in germ cells – is a paradigm of epigenetic gene control. The dysregulation of imprinted genes (a phenomenon referred to as "loss-of-imprinting") during early development leads to embryonic death or severe developmental syndromes and in the adult is associated with specific cancers and metabolic syndromes. Loss-of-imprinting is also frequently observed upon derivation and culture of pluripotent stem cells and represents on of the most significant hurdles for the biomedical use of these cells. We have developed genetically-engineered animal models and stem cell lines that allow studying the stability of genomic imprinting at the single-cell level in vivo and ex vivo. We are using this technology in combination with functional genomics (such as CRISPR screening) and genetics approaches to identify trans-acting factors and genetic variants that either protect or challenge physiological epigenetic states.


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