Karl Ekwall

Most of the cells in an adult individual are not in active cell division but in a cellular resting state called 'quiescence'. Even cancer cells can be in 'quiescence', which makes them resistant to chemotherapy. It is a problem because such cells give rise to new tumors after treatment. Epigenetic changes are different types of modifications to the genetic material that are needed so that the DNA sequence can be read correctly in different cell types. This is a prerequisite for normal development of the body's various tissues. In the project, we study epigenetic regulation of cellular quiescence and cancer. The goal of the proposed project is to understand how epigenetic changes affect cells in quiescence. We are particularly interested in understanding the function of a special type of epigenetic change called chromatin remodeling. The project is about two enzymes for chromatin remodeling: Paf1C (RNA Polymerase II associated protein) and Ino80 (Inositol requiring nucleosome remodeling factor). We have shown that Paf1C and Ino80 regulate the epigenetic stability of chromatin and that this is a prerequisite for cells to survive in quiescence. We use yeast cells and human skin cells as model systems for these studies. We want to map exactly how Paf1C and Ino80 interact and how they affect epigenetic, chromosomal states and gene expression in two different model systems. This basic knowledge may become important for future more effective chemotherapy treatments against cancer cells that are in quiescence. One of the proteins that make up Paf1C is called Leo1. Patients with low Leo1 levels survive their disease much better than patients with high Leo1 levels. In the project, we will study epigenetic effects of a drug (Ouabain) that inhibits Leo1. These results may contribute to the development of new tailored treatments against lung cancer.

Epigenetic regulation is based on various types of modifications of the genome (chromatin) that are needed for the same DNA sequence to be read in different ways in the> 250 different cell types that exist and this is a prerequisite for normal development and the body's function. The human 'epigenom' is a map of all these modifications and the map looks different depending on which cell type and tissue it comes from. A relatively newly discovered form of epigenetic regulation called 'nucleosome remodeling' is involved in this regulation that is done using SWI2 / SNF2 'chromatin transformation enzymes'. SWI2 / SNF2 enzymes are of central importance for epigenetic regulation and can thus control the epigenetic states of the cells by influencing the positions of the 'nucleosomes'. Nucleosomes are the cylindrical protein / DNA structures that pack the DNA into the chromosomes and which simultaneously carry the majority of the epigenetic modifications. The chromatin converting enzymes can turn off and turn on gene expression by moving on nucleosomes and thereby making the DNA sequence available for reading via transcription factors and RNA polymerase. The clinical benefit of the project is partly an increased basic understanding of epigenetic regulation with regard to the function of certain chromatin converting enzymes and the protein complex Paf1. This is a knowledge base that can be used to understand the mechanism of diseases with altered epigenetic states. In the longer term, these studies can lead to improved diagnostics, prognosis and treatment based on epigenetic mechanisms. The work on inhibitors directed against chromatin transformation enzymes can directly lead to new epigenetic treatments, for example in leukemia and prostate cancer.

All human cells contain the same DNA sequence. Despite this, the DNA sequence can be used in different ways in the> 250 different cell types that exist and this is a prerequisite for normal development and the body's function. Epigenetic regulation is based on various types of modifications of the genome (chromatin) that are needed for the DNA sequence to be read correctly. The human "epigenom" is a map of all these modifications and the map looks different depending on which cell type and tissue it comes from. One important question is how an epigenetic condition can change as cells differentiate (mature). A relatively newly discovered form of epigenetic regulation called "nucleosome remodeling" is involved in this regulation that is done with the help of "chrominoma conversion enzymes". These SWI2 / SNF2 enzymes are of central importance for epigenetic regulation and can thus control the epigenetic states of the cells by influencing the positions of the nucleosomes. Nucleosomes are the cylindrical protein / DNA structures in which the DNA is packaged in the chromosomes and which at the same time carries the majority of the epigenetic modifications. The chromatin converting enzymes can turn off and turn on gene expression by making the DNA sequence available for reading. We want to understand the role of the SWI2 / SNF2 enzymes in epigenetically programming the cells during differentiation. The work is important to understand the background to acute myeloid leukemia (AML). AML is caused by an epigenetic error programming where the SWI2 / SNF2 enzymes play an important role. In the slightly longer term, the work can give new hope for better diagnosis and treatment of acute myeloid leukemia and other blood disorders with epigenetic interference. We are also looking for new future drugs that can inhibit the activity of SWI2 / SNF2 enzymes. Our goal is to find new strategies for epigenetic cancer treatment.

All human cells contain the same DNA sequence. Despite this, the DNA sequence can be used in different ways in the> 250 different cell types that exist and this is a prerequisite for normal development and the body's function. Epigenetic regulation is based on various types of modifications of the genome (chromatin) that are needed for the DNA sequence to be read correctly. The human "epigenom" is a map of all these modifications and the map looks different depending on which cell type and tissue it comes from. One important question is how an epigenetic condition can change as cells differentiate (mature). A relatively newly discovered form of epigenetic regulation called "nucleosome remodeling" is involved in this regulation that is done with the help of "chrominoma conversion enzymes". These SWI2 / SNF2 enzymes are of central importance for epigenetic regulation and can thus control the epigenetic states of the cells by influencing the positions of the nucleosomes. Nucleosomes are the cylindrical protein / DNA structures in which the DNA is packaged in the chromosomes and which at the same time carries the majority of the epigenetic modifications. The chromatin converting enzymes can turn off and turn on gene expression by making the DNA sequence available for reading. We want to understand the role of the SWI2 / SNF2 enzymes in epigenetically programming the cells during differentiation. The work is important to understand the background to acute myeloid leukemia (AML). AML is caused by an epigenetic error programming where the SWI2 / SNF2 enzymes play an important role. In the slightly longer term, the work can give new hope for better diagnosis and treatment of acute myeloid leukemia and other blood disorders with epigenetic interference. We are also looking for new future drugs that can inhibit the activity of SWI2 / SNF2 enzymes. Our goal is to find new strategies for epigenetic cancer treatment.

All human cells contain the same DNA sequence. Despite this, the DNA sequence can be used in different ways in the> 250 different cell types that exist and this is a prerequisite for normal development and the body's function. Epigenetic regulation is based on various types of modifications of the genome (chromatin) that are needed for the DNA sequence to be read correctly. The human "epigenom" is a map of all these modifications and the map looks different depending on which cell type and tissue it comes from. One important question is how an epigenetic condition can change as cells differentiate (mature). A relatively newly discovered form of epigenetic regulation called "nucleosome remodeling" is involved in this regulation that is done with the help of "chrominoma conversion enzymes". These SWI2 / SNF2 enzymes are of central importance for epigenetic regulation and can thus control the epigenetic states of the cells by influencing the positions of the nucleosomes. Nucleosomes are the cylindrical protein / DNA structures in which the DNA is packaged in the chromosomes and which at the same time carries the majority of the epigenetic modifications. The chromatin converting enzymes can turn off and turn on gene expression by making the DNA sequence available for reading. We want to understand the role of the SWI2 / SNF2 enzymes in epigenetically programming the cells during differentiation. The work is important to understand the background to acute myeloid leukemia (AML). AML is caused by an epigenetic error programming where the SWI2 / SNF2 enzymes play an important role. In the slightly longer term, the work can give new hope for better diagnosis and treatment of acute myeloid leukemia and other blood disorders with epigenetic interference. We are also looking for new future drugs that can inhibit the activity of SWI2 / SNF2 enzymes. Our goal is to find new strategies for epigenetic cancer treatment.

Epigenetics was introduced as a theory in developmental biology in the 1970s and has evolved into a hot molecular biology research area. Epigenetics is about the hereditary properties of the cells that can be altered without changing the genetic information (the DNA sequence). Epigenetic regulation is based on various types of modifications of the genome (chromatin). So-called "nucleosomes" can be modified epigenetically. Nucleosomes are the cylindrical protein / DNA structures in which the DNA is packaged in the chromosomes. A newly discovered and exciting epigenetic regulation is called 'nucleosome remodeling' and is done using 'SNF2' enzymes. The project has two parts. In the first, we study so-called "SNF2" chromatin transformation enzymes in a model system to define their different basic functional mechanisms which are not yet known in detail. In man, there are no less than 53 different SNF2 chromatin converting enzymes and because of this great complexity we use a simpler cellular model system. Fission yeast has only 20 different SNF2 enzymes, which means that we can systematically study these with "genomic-wide" methodology. In the second part of the project, we study human SNF2 enzymes and, in particular, those involved in blood cell formation (hematopoiesis). To create a knowledge base regarding the function of SNF2 enzymes. To develop cancer epigenetics as a new area of research. To map the role of SNF2 enzymes in normal blood cell formation in humans. The goal is to understand their role in epigenetically programming the cells as they mature (differentiate). This work is important in understanding the background to acute myeloid leukemia (AML). AML is caused by an epigenetic error programming where the SNF2 enzymes play an important role. In the slightly longer term, the work can give new hope for better diagnosis and treatment of acute myeloid leukemia and other blood disorders with epigenetic interference.