EPFL scientists have carried out a genomic and evolutionary¹ study of a large and enigmatic family of human proteins, to demonstrate that it is responsible for harnessing the millions of transposable elements in the human genome. The work reveals the largely species-specific gene²-regulatory networks that impact all of human biology, in both health and disease. The human genome contains millions of sequences derived³ from so-called transposable elements, genetic⁴ units that “jump” around the entire genome. Long considered as junk DNA⁵, transposable elements are now recognized as influencing the expression of genes⁶. However, the extent of this regulation and how it is harnessed were so far unknown. EPFL scientists have now taken the first extensive look at a family of ~350 human proteins, showing that they establish a complex interplay with transposable elements to create largely human-specific gene regulatory networks. Published in Nature, the work also traces the evolutionary history of these proteins, and opens up a new dimension in genetics and medicine. 

 

The lab of Didier Trono at EPFL revealed a few years ago that a protein serving as cofactor to many KZFPs (KRAB-containing zinc-finger proteins) was involved in silencing transposable elements during the first few days of embryogenesis. Now he and his collaborators have carried out an extensive analysis of human KZFPs, retracing⁷ their evolutionary history and identifying their genomic targets.

 

The scientists combined phylogenetics – the study of evolutionary relationships between different species, with genomics — the study of how the genome of an organism conditions its biology. By comparing the genomes of 203 vertebrates, they first traced the origin of KZFPs back to a common ancestor of tetrapods (four-legged animals) and coelacanth, a fish that evolved over 400 million years ago. This evolutionary conservation of the KZFP-transposable element system hints to its fundamental importance.

 

Trono’s team then mapped out the genomic targets of most human KZFPs, finding that the greatest fraction recognizes transposable elements. “The vast majority of KZFPs binds⁸ to specific motifs⁹ in transposable elements,” says Trono. “For each KZFP we were able to assign one subset of transposable elements, and also found that one transposable element can often interact with several KZFPs. It is a highly combinatorial and versatile¹⁰ system.”

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