Simon Elsässer

The first lineage choice in human embryo development extra- and embryonic cell fates. Extraembryonic trophectoderm (TE) gives rise to placental tissues while the inner cell mass (ICM) progresses via the epiblast stage to form the fetus. The restriction of ICM cells to embryonic lineage capacity is crucial for ordered embryonic development, and concomitant development of extraembryonic support tissue from TE is crucial for survival of the embryo. These earliest steps are remarkably inefficient in humans: it is estimated that only one in three conceptions progress to live birth, with an early time window before and after implantation being the most crucial stages for a successful pregnancy. The aim of this project is to elucidate the mechanisms of the first cell fate decision and subsequent lineage determination by employing in vitro preimplantation models based on naïve human embryonic stem cells and 3D blastoids. The project will rely on quantitative epigenome profiling technology, functional perturbations, live cell imaging, and single-cell multimodal readouts to capture complex regulatory networks at play during early human development. We will more broadly elucidate how chromatin makeup dynamically changes as a function of the cell cycle and how cells integrate internal and external information to make cell fate decisions. Our research will further technology for dissecting complex developmental programs and provide insights into early human development and fertility.

Understanding fundamental principles that regulate the early human embryo has clinical value for reproductive technologies, congenital disease, and regenerative medicine. My lab and others have begun to uncover the molecular mechanisms controlling the first week of development but following implantation, we have very poor understanding beyond historic histological characterisations. We have learned a lot from the mouse, but human post-implantation development is very distinct from mouse. One example, following implantation a primate specific cell type fills the blastocoel cavity prior to gastrulation, the extra embryonic mesenchyme. This cell type is completely lacking in the mouse.New opportunities to study post-implantation development has emerged through extended blastocyst cultures and stem cell-based embryo models. In this project we will build a comprehensive spatial single cell transcriptional atlas of implantation, describing the cell types and the genes that control them. This resource will be critical to validate blastoids and post-implantation embryo models. Functionally we will use the transcriptional information and validated embryo models, together with genome editing to dissect regulators of the implantation event and lineage specification of the extra embryonic mesenchyme and amnion. Lastly, we will extend our recent studies of the epigenetic control through Polycomb Repressive Complex 2, histone deacetylation and X-chromosome inactivation in female embryos.

Short open reading frames, which encode small proteins or peptides, outnumber canonical open reading frames in the human genome by an order of magnitude, but extremely little is known about their function and disease relevance. This is because it was traditionally thought that smaller than normal proteins could have no function. But now our research and that of others shows that there is a huge, hitherto unknown, functional repertoire within short open reading frames. We search for small proteins and peptides that help cancer cells avoid chemotherapy. We are working with cancer cell lines for our first investigations. When we identify small proteins that make cancer cells grow better despite treatment, we generate molecular tools that can be used to look for these proteins in primary tumor samples and patients. We are evaluating whether the small protein can be targeted to a molecule, which can be turned into a chemotherapy. We hope our research will help cure cancers that currently elude the best treatments. We believe that identifying new drug targets is the key to preventing tumors from becoming resistant to chemotherapy.

The human genome can be described as an entire library of books, in which the letters of DNA form genes or chapters. Just as errors in the genetic language itself can cause diseases such as developmental disorders and cancer, diseases can be caused by reading from the wrong pages in the book. The role of chromate is to package the genome into available and unavailable domains, and thus ensure the overall organization of the genome. If this process fails, there is a risk of morbid changes in the genome, changes that can cause cancer and aging. Histone proteins package the double-stranded DNA molecules, which make up the human genome, into a very well-condensed state of the cell nucleus. The central role of the histones in the packaging process means that we believe that they are the key to regulating genetic information and constitute the actual molecular basis for indexing the genome with epigenetic information. Clinical studies have shown that several proteins that assist in the packaging of DNA are mutated in pancreatic tumors and brain tumors. We want to find out what these proteins (ATRX and DAXX) do at the molecular level, as well as their importance in curbing the development of tumors. Our research on the mechanism of epigenetic heritage will help us understand how abnormal epigenetic changes cause disease, for example, how tumor suppressor genes - important guardians of the genome - turn off when cancer occurs. We hope to find information at a molecular level to develop therapeutic strategies to correct such epigenetic mistakes.

The human genome can be described as an entire library of books, in which the letters of DNA form genes or chapters. Just as errors in the genetic language itself can cause diseases such as developmental disorders and cancer, diseases can be caused by reading from the wrong pages in the book. The role of chromate is to package the genome into available and unavailable domains, and thus ensure the overall organization of the genome. If this process fails, there is a risk of morbid changes in the genome, changes that can cause cancer and aging. Histone proteins package the double-stranded DNA molecules, which make up the human genome, into a very well-condensed state of the cell nucleus. The central role of the histones in the packaging process means that we believe that they are the key to regulating genetic information and constitute the actual molecular basis for indexing the genome with epigenetic information. Clinical studies have shown that several proteins that assist in the packaging of DNA are mutated in pancreatic tumors and brain tumors. We want to find out what these proteins (ATRX and DAXX) do at the molecular level, as well as their importance in curbing the development of tumors. Our research on the mechanism of epigenetic heritage will help us understand how abnormal epigenetic changes cause disease, for example, how tumor suppressor genes - important guardians of the genome - turn off when cancer occurs. We hope to find information at a molecular level to develop therapeutic strategies to correct such epigenetic mistakes.

The human genome can be described as an entire library of books, in which the letters of DNA form genes or chapters. Just as errors in the genetic language itself can cause diseases such as developmental disorders and cancer, diseases can be caused by reading from the wrong pages in the book. The role of chromate is to package the genome into available and unavailable domains, and thus ensure the overall organization of the genome. If this process fails, there is a risk of morbid changes in the genome, changes that can cause cancer and aging. Histone proteins package the double-stranded DNA molecules, which make up the human genome, into a very well-condensed state of the cell nucleus. The central role of the histones in the packaging process means that we believe that they are the key to regulating genetic information and constitute the actual molecular basis for indexing the genome with epigenetic information. Clinical studies have shown that several proteins that assist in the packaging of DNA are mutated in pancreatic tumors and brain tumors. We want to find out what these proteins (ATRX and DAXX) do at the molecular level, as well as their importance in curbing the development of tumors. Our research on the mechanism of epigenetic heritage will help us understand how abnormal epigenetic changes cause disease, for example, how tumor suppressor genes - important guardians of the genome - turn off when cancer occurs. We hope to find information at a molecular level to develop therapeutic strategies to correct such epigenetic mistakes.