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An experimental and bioinformatic toolbox for functional epigenomics and its application to epigenetically making and breaking a cancer cell

Periodic Reporting for period 4 - EpigenomeProgramming (An experimental and bioinformatic toolbox for functional epigenomics and its application to epigenetically making and breaking a cancer cell)

Reporting period: 2021-06-01 to 2021-11-30

The emergence of a complex organism requires an impressive degree of coordination and cooperation between cells. The human body is made up of about 30 to 40 trillion cells that work together to maintain bodily functions. These cells follow a genetic program of specialization and cooperation that provides for controlled growth as well as the planned death of cells that are no longer needed. This collaboration is only possible because almost all the cells of a body carry roughly the same genetic material. Darwinian selection therefore is suspended within the body: for the survival of individual’s genes it no longer matters whether a cell propagates itself or its sister cells take on this task. Therefore, the cells of the body do not compete for scarce resources, but complement and support each other.

But how do cells specialize when they all share the same genetic material? Evolution has chosen the second and third dimension: while the letters of the DNA remain unchanged, the DNA molecules in the cell are elaborately packaged, twisted, and wound up. This way, cells fit two meters of DNA into their microscopically small nuclei, and the packaging controls which genes can be used by a specific cell in the body. For example, an insulin-producing cell in the pancreas can activate its insulin gene at any time because it is freely accessible in the middle of the cell nucleus. In contrast, it cannot readily activate brain-specific genes; they are rolled up and locked away on the inner wall of the cell nucleus. This intricate level of regulation prevents the wrong genes from being inadvertently activated and thereby confusing the regulatory state of the cells. The additional layer of gene regulation in two and three dimensions is often referred to as "epigenetics" or "epigenomics".

Epigenetic gene regulation appears to be ubiquitous in cancer, in the sense that all cancers that have yet been studied in detail show widespread and cancer-specific epigenetic alterations: As a result of environmental influences or simply by chance, cells are sometimes epigenetically deprived of access to important genes. Normally the affected cells die and do no further damage. But sometimes it hits important genes that regulate the growth of the cell. Then it can happen that a single cell stops its cooperation with the organism and begins with unregulated growth - a tumor arises. In my laboratory at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, we investigate the role of epigenetic changes in the development of cancer. In the context of my ERC project, we have developed and applied wet-lab and computational methods that help us understand which of the many epigenetic alterations observed in cancer have a functional role.
1. Cancer epigenetics. We have investigated the epigenetic regulation in chronic lymphocytic leukemia (CLL), with a focus on epigenetic and gene-regulatory changes induced by the targeted cancer drug ibrutinib. This work has led to two major publications (Schmidl et al. 2019 Nature Chemi-cal Biology; Rendeiro 2020 Nature Communications).

2. Technology development. We have developed groundbreaking technology that enables functional biology at scale, based on the combination of CRISPR screening and single-cell sequencing. This work has led to two major publications: Datlinger et al. 2017 Nature Methods (introducing CROP-seq) and Datlinger et al. 2020 Nature Methods (introducing scifi-RNA-seq).

3. Exploitation and dissemination. We have completed a “methods primer” on high-content CRISPR screening (Bock et al. 2022 Nature Reviews Methods Primers), coordinating a high-profile consortium to provide a broad introduction into such screens. Moreover, we have commercialized the CROP-seq technology for single-cell CRISPR sequencing, which is used by biotechnological and pharmaceutical companies.
The project has substantially advanced the state of the art in cancer epigenetics and high-throughput technology. Most notably, the CROP-seq and scifi-RNA-seq technologies developed in the course of this project enable functional biology at scale and are broadly useful for biomedical research.
CROP-seq - a breakthrough method for CRISPR single-cell sequencing
DNA methylation - an epigenetic mark closely linked to cancer