Understanding life's recipe book: genetic jigsaws

Genes are the fundamental instructions for life – a complex recipe book that is being deciphered by molecular biologists and biochemists. It’s been just over 50 years since the double helix structure of DNA was discovered and in that time we’ve made huge leaps in our understanding of genes.

Professor Merlin Crossley, from the School of Molecular Bioscience, investigates how DNA-binding proteins turn genes on and off. He is interested in understanding how the regulation of gene expression controls cellular development and how the breakdown of regulation leads to disease. His work spans diseases of the blood, the regulation of fat and the genes in cancer and in stem cells.

Crossley focuses on three DNA-binding proteins that regulate gene output – Basic Kruppel-like Factor (KLF3), C-terminal Binding Protein (CtBP) and Zinc Finger Protein 217 (ZNF217).

“KLF3 is one of a family of proteins, which were the first mammalian DNA-binding proteins to be characterised. Our team has concentrated in KLF3 working out how it regulates gene expression, what biological processes it controls and how its activity is controlled in the body,” explains Crossley.

“Found in high concentrations in immature red blood cells, fat cells and cells of the immune system, KLF3 has been linked to the regulation of haemoglobin synthesis, fat accumulation, and B cell lymphomas – a common form of cancer.”

“KLF3 turns genes off by recruiting CtBP, which works to recruit enzymes that modify histones – the proteins that DNA is wrapped around – and alter the way DNA is packaged,” says Crossley.

“ZNF217 binds to CtBP and is also involved in gene repression. The gene encoding ZNF217 is amplified – there are more copies of this gene present – in numerous human cancers, most notably breast cancer.”

Crossley’s group is investigating the role of the zinc fingers of ZNF217 in DNA and protein interactions, in collaboration with Dr Joel Mackay.

“Zinc fingers are protein domains that bind to DNA. At their centre is a zinc metal ion, surrounded by a structure of protein strands. Without the zinc ion, the finger unfolds and falls apart,” says Crossley.

“By understanding how these DNA binding proteins regulate processes associated with cancer, we may one day be able to control cellular proliferation.”

“Our aim is to control the expression of specific genes. If you can control genes, you can do almost anything in biology. The diversity of life is an illustration of this. Much evolutionary change is not related to the creation of new genes, but rather with the alteration of existing genes,” concludes Crossley.