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Type 2 diabetes (T2D) is a heterogenous disease with chronic inflammation being a feature of recently identified T2D subtypes. Suspected major drivers of these inflammatory subtypes are monocytes. An intriguing hypothesis is that monocytes acquire epigenetic changes (not encoded by the genome DNA) in response to diverse metabolic-inflammatory signals already at early diabetic stages. This establishes a memory that pre-disposes monocytes to further trigger the inflammatory T2D state and its complications including cardiovascular diseases. To shed light on the underlying mechanisms, we will study the role of so-called enhancers and silencers, regulatory elements that control how genes are turned on and off, in monocytes. Our studies may help to overcome a knowledge gap as the monocyte enhancer and silencer landscape and its T2D-associated alterations are currently unknown. Such alterations may become translational important as they may lead to new targets for T2D treatment. _x000D_ _x000D_ _x000D_ _x000D_

The purpose of our research is to contribute to a deeper understanding of closely linked transcriptional and epigenetic mechanisms underlying health and disease. We are particularly interested in the role of coregulators, which via controlling transcription factors and chromatin states are essential components of these mechanisms.With an emphasis on a fundamental corepressor complex implicated in metabolic and inflammatory disease pathways, we recently made the unexpected discovery that corepressors operate at both enhancers and silencers to trigger alternative macrophage gene expression programs.Here we propose research within three aims to address the following key hypotheses emerging from this discovery:Corepressors are essential components of topologically associating domains (TADs) to control chromatin dynamics and transcription, in cooperation with transcription factors and other coregulators.Corepressors mark TAD-intrinsic silencers in different signaling contexts and can be exploited for genome-wide silencer screenings.Corepressor alterations trigger epigenetic remodeling and memory mechanisms that causally link type 2 diabetes to cardiovascular diseases such as atherosclerosis.

Epigenetic changes play a decisive role in the development of cancer and are assumed to be a cause of increased cancer risk in metabolic diseases such as fatty liver and cardiovascular diseases and also in obesity. Epigenetics means on top of genetics and deals with modifications of the genetic material that do not change the DNA sequence in the genome. These modifications determine where and when genes are turned on or off and can be part of an epigenetic memory that affects the cells' function and communication with the environment. It is likely that epigenetic differences are a reason why individual people are at different risk of developing cancer in connection with metabolic diseases. Our project aims to identify epigenetic mechanisms and changes that contribute to liver cancer associated with obesity and non-alcoholic fatty liver disease, which are established risk factors. Our unique approach is to study two key components: regulatory DNA elements that control gene expression, and proteins that bind to these elements and influence the structure and function of the genome. We will apply the latest genome-wide methods to map epigenetic changes in different cell types in the liver (hepatocytes, macrophages), both in mouse models and in human liver cells, in collaboration with clinical researchers. We hope that our research results will contribute to a deeper understanding of the mechanisms that link metabolic diseases and cancer, especially liver cancer, where knowledge of epigenetic causes of disease is currently completely lacking. Although our research is pre-clinical, we will bring new knowledge and methodology that will benefit patients. Our results can, for example, lead to new diagnosis methods by identifying epigenetic biomarkers, and to new forms of therapy by stimulating the development of new drugs that counteract epigenetic changes that cause cancer.

The onset of metabolic diseases such as obesity, diabetes, fatty liver and cardiovascular disease are related to changes in metabolism but also have inflammatory causes. Inflammation is believed to be an important factor linking metabolic diseases and various cancers. Recent years of research suggest that changes within the epigenome, through chromatin modifications linked to gene expression, play a crucial role. Individual differences in the structure and function of the epigenome can be a reason why individual people react differently to similar nutritional and environmental challenges in developing metabolic diseases and cancer. Our studies aim to better understand how changes in the epigenome contribute to an inflammatory disease environment. In addition, we try to develop concept models for future therapeutic treatments by modifying the epigenome's components. To achieve these goals, we focus on two key components: "coregulators" i.e. proteins that affect the structure and function of the epigenome, and ‘enhancers’, i.e. cell type-specific enhancers of gene expression. We will apply modern genomic methods to map the epigenome in various disease processes in mice as well as in human tissues, through collaboration with clinical researchers. We hope that our research results will contribute to a deeper understanding of the intricate relationships between metabolic diseases, inflammation and cancer at the molecular and physiological level. In addition, we hope that our concept models will have therapeutic significance for the development of new drugs that can counteract or correct disease-related epigenomal changes.

The onset of metabolic diseases such as obesity, diabetes and arteriosclerosis are related to changes in metabolism, but also have inflammatory causes. The disease-related correlation between metabolism and inflammation is referred to as metaflammation and is today a fundamental risk factor for the development of various cancers. Recent years of research suggest that changes within the epigenome, through chromatin modifications linked to gene expression, play a crucial role. Epigenomic differences are thought to be an important reason why individuals react differently to similar nutritional and environmental challenges in developing cancer. Our research aims to better understand how epigenomic processes shape a metaflammatory disease environment, and vice versa, and can lead to cancer. We try to answer these questions by studying co-regulators, proteins that modify chromatin in conjunction with transcription factors, in tissue-specific knockout mouse models and in human tissue. We will apply and develop modern genomic strategies, particularly ChIP sequencing, to map the epigenome in various disease pathways in mice as well as in human tissue and isolated cell types. In addition to basic bio̽»¨¾«Ñ¡ research, we plan to expand our clinical collaboration. We hope that our research results will contribute to a deeper understanding of the intricate relationships between metabolism, inflammation and cancer at the molecular and physiological level. In addition, we hope that the project will open up new opportunities to treat and prevent metabolic diseases and cancer. The GPS2 complex is one of the first examples of an anti-inflammatory coregulator that can modify the epigenome and whose expression and function are affected by metabolic diseases. This could lead to therapeutic possibilities to counteract metaplasty by restoring the function of the complex and thereby inhibiting the development of cancer.

The onset of metabolic diseases such as obesity, diabetes and arteriosclerosis are related to changes in metabolism, but also have inflammatory causes. The disease-related correlation between metabolism and inflammation is referred to as metaflammation and is today a fundamental risk factor for the development of various cancers. Recent years of research suggest that changes within the epigenome, through chromatin modifications linked to gene expression, play a crucial role. Epigenomic differences are thought to be an important reason why individuals react differently to similar nutritional and environmental challenges in developing cancer. Our research aims to better understand how epigenomic processes shape a metaflammatory disease environment, and vice versa, and can lead to cancer. We try to answer these questions by studying co-regulators, proteins that modify chromatin in conjunction with transcription factors, in tissue-specific knockout mouse models and in human tissue. We will apply and develop modern genomic strategies, particularly ChIP sequencing, to map the epigenome in various disease pathways in mice as well as in human tissue and isolated cell types. In addition to basic bio̽»¨¾«Ñ¡ research, we plan to expand our clinical collaboration. We hope that our research results will contribute to a deeper understanding of the intricate relationships between metabolism, inflammation and cancer at the molecular and physiological level. In addition, we hope that the project will open up new opportunities to treat and prevent metabolic diseases and cancer. The GPS2 complex is one of the first examples of an anti-inflammatory coregulator that can modify the epigenome and whose expression and function are affected by metabolic diseases. This could lead to therapeutic possibilities to counteract metaplasty by restoring the function of the complex and thereby inhibiting the development of cancer.

The onset of metabolic diseases such as obesity, diabetes and arteriosclerosis are related to changes in metabolism, but also have inflammatory causes. The disease-related correlation between metabolism and inflammation is referred to as metaflammation and is today a fundamental risk factor for the development of various cancers. Recent years of research suggest that changes within the epigenome, through chromatin modifications linked to gene expression, play a crucial role. Epigenomic differences are thought to be an important reason why individuals react differently to similar nutritional and environmental challenges in developing cancer. Our research aims to better understand how epigenomic processes shape a metaflammatory disease environment, and vice versa, and can lead to cancer. We try to answer these questions by studying co-regulators, proteins that modify chromatin in conjunction with transcription factors, in tissue-specific knockout mouse models and in human tissue. We will apply and develop modern genomic strategies, particularly ChIP sequencing, to map the epigenome in various disease pathways in mice as well as in human tissue and isolated cell types. In addition to basic bio̽»¨¾«Ñ¡ research, we plan to expand our clinical collaboration. We hope that our research results will contribute to a deeper understanding of the intricate relationships between metabolism, inflammation and cancer at the molecular and physiological level. In addition, we hope that the project will open up new opportunities to treat and prevent metabolic diseases and cancer. The GPS2 complex is one of the first examples of an anti-inflammatory coregulator that can modify the epigenome and whose expression and function are affected by metabolic diseases. This could lead to therapeutic possibilities to counteract metaplasty by restoring the function of the complex and thereby inhibiting the development of cancer.

The onset of metabolic diseases such as obesity, diabetes, arteriosclerosis and various cancers have metabolic and inflammatory (metaplastic) components. Recent years of research indicate that nuclear receptors (proteins that bind metabolites and hormones and regulate gene expression) play a crucial role in metaflammatory signaling pathways and can inhibit inflammatory gene expression. In addition, co-regulators (proteins that modify chromatin) link nuclear receptor signaling to epigenomic mechanisms. Obviously, deeper insights into anti-inflammatory signaling pathways are of utmost importance for therapeutic intervention. Our research focuses on fundamental issues regarding anti-inflammatory nuclear receptor signaling and disease mechanisms. We have recently discovered a protein (GPS2) within the corepressor complex of importance for the link between metabolism and inflammation via nuclear receptors. We now want to move on to show the relevance of "metaflammatory" disease mechanisms. We will use tissue-specific GPS2 knockout mice, experimental disease and cancer models, and genome-wide techniques. We also want to investigate the interaction between the GPS2 network with the estrogen receptor and inflammatory signaling in breast cancer. The proposed research will lead to a better understanding of how changes in nuclear receptor signaling, their anti-inflammatory networks, and their interactions with the epigenome can alter gene expression and thus contribute to the onset of metabolic diseases and cancer. In addition, we hope that the results from the project will have therapeutic significance for the development of new anti-inflammatory drugs. For example, one could imagine that drugs that specifically affect the interaction between core receptors and corepressors will counteract inflammation and thus inhibit the development and progression of cancer.