New Danish research shows that stem cells deactivate many genes related to bone cells when they are on their way to becoming fat cells. This research is a masterpiece in basic science that can also eventually be used to improve stem cell therapy and understand various diseases.
Hundreds of genes must be activated or deactivated when stem cells become either bone cells or fat cells. This occurs in an organized and well-orchestrated network of mechanisms for regulating transcription, and Danish researchers have gained great insight into this process for the first time.
Transcription factors are proteins that bind to the DNA near the genes they regulate, and the research shows that many more changes in transcription factors are required to make a fat cell than to make a bone cell.
“We were surprised that stem cells, whether from bone marrow or from fatty tissue, resemble bone cells as much as they do. Many transcription factors involved in developing bone cells are already active in stem cells, so the stem cells are genetically preprogrammed to become bone cells. This means that these transcription factors must be deactivated and new fat cell–selective transcription factors activated before a stem cell can become a fat cell. Stem cells can form fat cells in several types of tissue. However, these stem cells appear to more closely resemble bone cells than fat cells,” explains Susanne Mandrup, Professor, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense.
The new research results were recently published in Nature Genetics.
Can ultimately be developed into therapies to combat disease
This basic science discovery is important for understanding diseases in which stem cells lose their potential to repair and replace various types of tissue. Bones, for example, are constantly being formed and broken down, and failure of the processes that form the bones can lead to osteoporosis.
The discovery also adds knowledge that is vital for developing stem cell therapy to treat people with diseases in which the body lacks fat cells or bone cells. Doctors will hopefully be able to combat osteoporosis at some point by stimulating more stem cells to develop into bone cells. Doing this requires knowing how to optimally stimulate the process of maturing the stem cells.
“Most studies on how transcription factors influence the development of stem cells have examined individual transcription factors, but we have investigated the importance of all transcription factors and have thus created more comprehensive insight into how the process takes place. This is important for basic scientific insight into stem cell development but also provides knowledge that could be used to optimize stem cell therapy in various contexts,” says Susanne Mandrup.
Developing stem cells into fat cells or bone cells involves 200 factors
All cells in the human body contain the same DNA and the same genes. What defines the properties of a cell is which genes in the cell can be transcribed and translated into proteins. For a stem cell to develop into a specific cell type, it must activate the specific genes characteristic of that cell type. Transcription factors govern this process.
Susanne Mandrup’s research group investigated which transcription factors are involved in developing bone cells and fat cells. Advanced bioinformatic analysis revealed that, of the 933 transcription factors that appear to be involved in developing bone cells or fat cells, 202 transcription factors stimulate bone formation, and most of these are already active in the stem cell stage. Interestingly, these factors must be deactivated for a stem cell to develop into a fat cell, thus functioning as an on–off switch.
“We used a bioinformatic program we published last year that was developed by my talented postdoctoral colleague, Jesper Grud Skat Madsen. This program uses machine learning to identify which transcription factors play a role in regulating gene expression in a cell and during cellular development,” explains Susanne Mandrup.
Overall structure of DNA determines whether genes are expressed
The researchers initially examined the changes in the structure of chromatin when stem cells become either fat cells or bone cells.
Chromatin is the protein scaffold in which DNA is organized in the nucleus, and this structure and the accessibility of the DNA determine which genes in DNA can be transcribed.
Depending on the chromatin structure, various transcription factors can access the relevant genes that direct a stem cell towards becoming either a fat cell or a bone cell.
“Here we discovered that bone cells have much in common with stem cells. Not just stem cells from the bone marrow but also stem cells from the fat tissue or muscles,” says Susanne Mandrup.
Bioinformatics makes sense of the complexity
The researchers investigated whether they could use bioinformatics to predict which transcription factors the stem cells would activate or deactivate to become fat cells or bone cells.
More precisely, the researchers determined the position of the enhancers, which are the regulatory sequences in DNA where the transcription factors bind.
Some enhancers recruit transcription factors that activate genes related to bone cells, whereas others recruit transcription factors that activate genes related to fat cells.
“We have been able to predict which enhancers are important for the upregulation and downregulation of genes as the stem cells develop into bone cells or fat cells. Interestingly, some of these enhancers are already known based on genome variation studies to play a role in predisposing to various diseases,” says Susanne Mandrup.
”Osteogenesis depends on commissioning of a network of stem cell transcription factors that act as repressors of adipogenesis” has been published in Nature Genetics. In 2018, the Novo Nordisk Foundation awarded a Challenge Programme grant of DKK 60 million to Susanne Mandrup, Professor, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense for the project ADIPOSIGN – Center for Adipocyte Signaling.
