Genome Organization and Function
Group Leader: Dr Suzana Hadjur
Despite the vast amount of information that the sequencing of our genome has brought, our nucleus is still a mysterious place. The mammalian genome is estimated to contain 22,000 genes which reside on 46 chromosomes. In order to contain our genome within nuclear space, DNA molecules must undergo many levels of organization resulting in discrete nuclear ‘environments’. Moreover, this organization must be dynamic and responsive as cells go about the regular business of producing proteins, responding to their environment and dividing. How this complex organization is orchestrated is an important question in genome biology.
- Dr Sevil Sofueva
- Dr Wen-Ching Chan
- Matteo Vietri Rudan, PhD student
- Dimitra Georgopoulos, PhD student
All cells contain the same DNA content, however the activity of particular genes changes during development leading to specialized cells and tissues. Understanding how gene activity is controlled lies at the heart of any exploration of development. Growing evidence indicates that the spatial organization of the genome, ie. the three-dimensional configuration and localization of genes within the nucleus, plays an important role in the systems that control gene activity.
We are interested in understanding the fundamental principles behind genome organization in space and time, the proteins involved in establishing and maintaining this organization and how it changes during cellular development and disease. We use cellular biology and high-resolution molecular approaches to gain insight into how the architectural organisation of the nucleus and regulation of gene activity are functionally linked in mammalian cells.
Protein-DNA interactions are the basis for most levels of chromatin organization and many proteins which have structural functions act by binding to specific genomic regions. We focus our current studies on the role of Cohesin proteins. Cohesin proteins are integral components of chromosome structure and are essential for ensuring daughter chromatids are paired immediately after replication and prior to separation at mitosis. In addition to this, it is increasingly clear that cohesin proteins participate in multiple mechanisms necessary for proper cellular behaviour which include interphase genome organization, control of gene expression and development.
The DNA binding protein CTCF has long been recognized as playing a central role in the organization of chromatin, regulating the ability of DNA elements involved in gene expression to communicate. Together with supporting work from other groups, our observations linked CTCF with cohesins and provided an explanation for how a protein complex that mediates sister chromatin cohesion is involved in regulating gene expression. This now leads to new questions about how cohesin-based chromatin topology influences gene activity.
Insight into how cohesin proteins work will lead to a better understanding of many aspects of chromosome biology as well as a deeper knowledge of developmental genetic diseases such as Roberts and Cornelia de Lange syndromes (caused by mutations in cohesin subunits) and cancer, where gene deregulation and anueploidy play a critical role.
Sofueva S and Hadjur S. (2011) Cohesin mediated chromatin interactions – into the third dimension of gene regulation. Briefings in Functional Genomics. Brief Funct Genomics. 2012 Jan 25. Pubmed
Hadjur S, Williams LM, Ryan NK, Cobb BS, Sexton T, Fraser P, Fisher AG, Merkenschlager M. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature. 2009 Jul 16;460(7253):410-3. Pubmed
Bowers SR, Mirabella F, Calero-Nieto FJ, Valeaux S, Hadjur S, Baxter EW, Merkenschlager M, Cockerill PN. A conserved insulator that recruits CTCF and cohesin exists between the closely related but divergently regulated interleukin-3 and granulocyte-macrophage colony-stimulating factor genes. Mol Cell Biol. 2009 Apr;29(7):1682-93. Pubmed
Parelho V*, Hadjur S*, Spivakov M, Leleu M, Sauer S, Gregson HC, Jarmuz A, Canzonetta C, Webster Z, Nesterova T, Cobb BS, Yokomori K, Dillon N, Aragon L, Fisher AG, Merkenschlager M. (2008) Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell. 2008 Feb 8;132(3):422-33. Pubmed
McMahon KA, Hiew SY, Hadjur S, Veiga-Fernandes H, Menzel U, Price AJ, Kioussis D, Williams O, Brady HJ. (2007) Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell. 2007 Sep 13;1(3):338-45. Pubmed