Transforming Cell States to Cure Bladder Disease
Carl Fishwick at work in the lab. Photo by Phil Roberts, Department of Biology, University of York.
Scientists have begun to unlock the genetic code to understand how the lining of the bladder functions as a barrier to store urine - paving the way for possible new treatments for chronic bladder diseases such as interstitial cystitis and cancer.
Using human cells, they have mapped how different proteins bind along the DNA to control which genes are active during barrier formation.
The inside of the bladder is covered by a specialised epithelial cell lining called the urothelium, which functions as a self-regenerating barrier to urine. The delicate balance between urothelial tissue repair and specialisation becomes disrupted in chronic diseases of the bladder.
A study, led by the University of York in collaboration with the Earlham Institute (EI) and published in Nature’s Cell Death and Differentiation, uses lab-grown normal human urothelial cells to investigate the process of urinary barrier formation.
Cells of the body carry the same genetic code in the form of DNA, but epigenetic programming means that different sets of genes are used to make different specialised tissues. Which genes are active in a particular tissue is partly decided by proteins called transcription factors (TFs)1 which bind along the DNA and control whether genes are switched on or off.
The York research team had previously shown that human urothelial cells could be grown as non-specialised cells in the laboratory to form a functional barrier. They had found that some of the important genes involved in this process encoded TF proteins, but had assumed that all TFs acted together and in the same direction.
Using a bioinformatics approach to map TF binding to the DNA, the Earlham Institute revealed that the TFs are actually arranged in a more complex or non-hierarchical pattern, where some may even compete for binding to the same DNA regions at different stages of the cell specialisation process.
Lead author of the study, Professor Jennifer Southgate, Director of the Jack Birch Unit of Molecular Carcinogenesis (JBUMC) in the University of York’s Department of Biology, said: “Using experimental methods to silence individual TF genes, we confirmed that TFs interact to define whether cells become specialised or non-specialised. In particular, we have shown one TF (called P63) is dominant in the non-specialised cells.
“It may sound esoteric, but it really is important to understand this process, particularly which transcription factors bind where and when, as this information provides the key to manipulating stem or precursor cells to form fully functional tissues for use in restorative medicine.
“This understanding of how TFs drive cell specialisation decisions will also help guide the search for drugs which can transform urothelial cell states as a therapeutic option.”
Dr Janet Higgins in the Swarbreck Group at the Earlham Institute, who led the study’s bioinformatics analysis, said: “Using specialist sequencing-based strategies and next-generation platforms within our Platforms and Pipelines Group, supervised by Lawrence Percival-Alwyn, we worked together with the Jack Birch Unit (JBU) to investigate the in-depth actions of the different TFs across the whole urothelial genome, by mapping their protein-binding activity along the DNA.”
The urothelial experiments were designed and carried out by Dr Carl Fishwick as part of his PhD at the University of York, using the normal human urothelial (NHU) cell models developed in the JBU. From the data generated, EI were able to identify transcription factors and chromatin (protein/DNA compound) dynamics driving cell differentiation, some of which were confirmed in further experiments in the JBU.
Dr Fishwick, added: “A key finding was that binding sites for different transcription factors were often co-located along the genome. This means that transcription factors could either compete or co-operate for binding to the same DNA regions. This can explain how cells mature within a tissue as transcription factors change. Our experiments also show that if a particular transcription factor is over-represented or absent, this can change the balance of gene expression in a cell and lead to disease.”
Changing Lanes: Algorithm Helps AI Drive More Like HumansNews
For self-driving cars, algorithms for changing lanes are beset by one of two problems. Either, they rely on detailed statistical models of the driving environment, which are too complex to analyze on the fly; or they’re so simple that they can lead to impractically conservative decisions, such as never changing lanes at all. Now a new algorithm hopes to split the difference, allowing aggressive lane changes than the simple models do but relies only on immediate information about other vehicles’ directions and velocities to make decisions.
Schizophrenics' Blood Contains RNA From More MicrobesNews
The blood of schizophrenia patients features genetic material from more types of microorganisms than that of people without the debilitating mental illness, research at Oregon State University has found. What’s not known is whether that’s a cause or effect of the severe, chronic condition that strikes about one person in 100.READ MORE
Faulty Gene Leads to Alcohol-Induced Heart FailureNews
A faulty gene interacts with alcohol to accelerate heart failure in susceptible patients, a study suggests. This dangerous interaction can occur even when only moderate amounts of alcohol have been consumed.READ MORE
Comments | 0 ADD COMMENT
2nd Annual Artificial Intelligence in Drug Development Congress
Sep 20 - Sep 21, 2018