Research project supported by the Swedish Research Council.
With our research, we want to increase the understanding of how a cell remembers and passes on which gene expressions to use after a cell division. To answer these questions, we study two gene regulatory systems in fruit flies that recognise and regulate two specific chromosomes. Understanding how chromosomes and chromosome-specific regulatory mechanisms have evolved over millions of years is central to explain the mechanisms that govern that our genome can coordinately express the right genes at the right time.
In both humans and flies, females and males have different sets of sex chromosomes. This leads to a difference between the sexes in the dose of the thousands of genes located on the X chromosome. Even though males have an X chromosome and females have two, the vast majority of genes should be expressed equally in both sexes and also in the right amount in relation to all other genes on other chromosomes.
Both in humans and the fruit fly, the compensation of gene dose is carried out by special regulatory systems referred to as dosage compensation systems. These regulatory systems (protein/RNA complexes) can somehow identify all genes on a specific chromosome and, in addition, regulate their expression in a coordinated manner. When the cell then divides into daughter cells, the correct gene expression must be remembered and passed on, which usually takes place by elaborated regulation of the packaging of DNA from different genes.
The research area that studies how cells remember which gene expression to use after cell division and how DNA is packed is called epigenetics. Epigenetics concerns how a cell reads which part of the genome, which genes, to use and how that information is then passed on when the cell divides. This memory is required for cells to “remember” which tissue they belong to and is called an “epigenetic memory” because it is not caused by differences in the DNA sequence itself.
We have previously isolated a gene encoding the chromosome-specific protein Painting-of-Fourth (POF), which specifically binds to chromosome 4 in fruit flies. Until then, chromosome-specific proteins was only been described linked to sex chromosomes, e.g., the X chromosome in humans and the fruit fly. The POF protein and its binding to chromosome 4 are therefore controversial since POF represents a chromosome-specific regulatory mechanism on a non-sex chromosome, thereby raising questions linked to the integrity of chromosomes and also the evolution of chromosomes and chromosome-specific mechanisms. The classical view has been that the division of the genome into chromosomes is a way of organising the genome.
Our results suggest that chromosomes may also have unique chromosome-specific functions that will affect epigenetic memory and these are the functions our research focuses on. Understanding how chromosomes and chromosome-specific regulatory mechanisms have evolved over millions of years is central to investigating the mechanisms that govern the proper expression of our genome in a coordinated manner. We have described the binding of POF to chromosome 4 and we know in detail which genes POF binds to. We now want to understand how POF and the dosage compensation system for the X chromosome can recognise genes chromosome-specific, how they can regulate the expression of these genes, and how these chromosome-specific systems evolve.
Our focus over the next few years is to identify which factors contribute to chromosome-specific protein/RNA complexes finding the right chromosome and binding to the right genes and sorting out the mechanisms that then allow these genes to be properly expressed. We also want to sort out the molecular mechanisms used to regulate an entire chromosome in a coordinated manner and how these mechanisms are linked to the correct distribution of the genome during cell division.
Non-coding RNA molecules and repeated sequences that often originate from mobile elements are a recurring theme in the processes we are interested in looking into. We will therefore prioritise identifying and analysing the function of the RNA molecules we now associate with the function of POF. We use fruit flies as a model system, which allows us to conduct our experiments on several different species where we know their evolutionary kinship. With our research, we hope to answer questions about how epigenetic systems are recruited into specific chromosomes or regions, and how these systems evolve and function. The strength of our model is that it is unique, while at the same time it will most likely show general principles.