Integrating genome structure and function View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2011-2018

FUNDING AMOUNT

4757616 GBP

ABSTRACT

Each human cell contains 2m of DNA, yet our genome has to function within the context of the cell nucleus that is only 10 thousandths of a mm in diameter. This remarkable feat of packing is achieved by folding the DNA sequence up with proteins, to form a structure called chromatin. We now realise that chromatin not only allows the DNA to fit inside of the cell, but that it also controls the way that the DNA is read. Using a combination of biochemistry and microscopy, we are investigating what different chromatin structures there are in mammals, and how they are normally regulated and changed during development to allow different sets of genes to be switched on and off. Once we understand the chromatin architecture of the normal genome, this will allow us to understand how altered chromatin structure can contribute to disease. Technical Summary We want to understand how chromatin is organized in the human cell nucleus, how this influences gene expression, and how it is altered during normal development and in disease. A range of technical approaches (biochemical, biophysical and cytological) now allows us to analyse multiple levels of chromatin structure, from the nucleosome through to nuclear organisation. Combined with the use of genomic microarrays, this means that we can determine chromatin structures, not only at individual genes, but also across large regions of the genome. An example of the latter are Hox loci, which encode genes important for patterning of the developing embryo. To study how chromatin structures are changed during early embryonic development, we use the mouse as a model system, taking advantage of pre-existing models for Hox gene regulation. We have recently begun to uncover alterations in normal spatial genome organization in human diseases. As well as observing the way that the genome is normally organized, we have developed a method to experimentally alter the spatial organization of the human genome within the nucleus in tissue culture cells. We have used this system to show that recruiting genes to the nuclear periphery is sufficient to mediate their transcriptional repression. We suggest that spatial organization is used to regulate gene expression during mammalian development. Lastly, we complement our study of the organisation of DNA by analysing the function of specific nuclear proteins that are involved in chromatin structure and gene regulation, and that we have identified by gene-trapping in mouse embryonic stem cells. More... »

URL

http://gtr.rcuk.ac.uk/project/18D88475-3494-40CC-8E1F-92BBC867714B

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