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They were forged in an ancient battle that pitted our ancestors’ genes against parasitic DNA from retro-viruses. The victors: a group of proteins known as C2H2-ZF which have the power to turn genes on or off. The vanquished: dormant vestiges that now serve as docking stations for their former foe. 

Thanks to Professor Tim Hughes, a professor at the University of Toronto’s Donnelly Centre, we know their story.

Hughes and his team did the first systematic study of the largest group of human transcription factors – C2H2-ZF – which was recently published in . 

C2H2-ZF are a type of protein that play an important role in development and disease. They have the ability to switch genes on or off – by binding precise sites on the DNA near their target genes before exerting control over their activity.

Thousands of genes are switched on or off at any given time, in a tightly orchestrated fashion. Knowing the rules of this process is crucial because, when it fails, diseases such as cancer can occur.

Despite their importance, C2H2-ZFs have been largely unexplored because they are abundant and diverse – which makes them hard to study. First, there are more than 700 proteins – around three per cent of all human genes – in the C2H2-ZF group. Second, most human C2H2-ZF proteins are very different from those in other organisms, like mice. This means scientists couldn’t apply insights gained from animal studies to human C2H2-ZFs. 

The Hughes team found the reason for this: many C2H2-ZF evolved to defend our ancestral genome from damage caused by so-called “selfish DNA.”
 
Selfish DNA are bits of parasitic DNA whose only purpose is to multiply; a kind of virus for our genome. Almost half the human genome is made of selfish DNA, which likely came from ancient retro-viruses that – like modern versions – inserted their DNA into the host’s genome. They seize a cell’s resources to make copies of themselves, which they insert randomly across the genome – causing harmful mutations along the way. When selfish DNA is passed on to the next generation, it becomes known as endogenous retro-elements (EREs).

Hughes’ data suggest C2H2-ZFs initially evolved to switch off EREs. As new EREs invaded the genome of our lizard-like ancestor, C2H2-ZFs arose to prevent them from disrupting gene function.

“What I think was not appreciated until this study is that retro-elements are really a driving force in the evolution of transcription factors themselves. All mammals have a whole bunch of custom transcription factors that came about to silence the EREs,” said Hughes, who is also a professor in U of T’s department of molecular genetics and a senior fellow of the Canadian Institute for Advanced Research. “But the EREs and these new transcription factors are different even for different vertebrates.” 

EREs are now harmless because they are millions of years old and they lost their ability to multiply and move around. 

The C2H2-ZFs, on the other hand, found new jobs.

C2H2-ZF proteins began using the EREs scattered across the genome as DNA docking sites, from which they could take control of nearby genes. The conquered EREs were finally enslaved.

This study greatly expands our understanding of how C2H2-ZFs evolved and how they work today, said Hughes, adding that the more researchers know about them, the more they will be able to use them to diagnose, prevent or treat diseases that occur when gene regulation fails.