The proteins that domesticated our genomes

epfl scis ‘ve carried out a genomic and evolutionary study offa large and enigmatic family of human proteins, to demonstrate that tis responsible for harnessing the millions of transposable essentialisms inna human genome. the work reveals the largely species-specific gene-regulatory networks that impact all of human biology, in both health and disease.

the human genome contains millions of sequences derived from so-called transposable essentialisms, genetic units that “jump” round the entire genome. long pondered as junk dna, transposable essentialisms are now recognized as influencing the expression of genes. however, the extent of this regulation and how tis harnessed were sfar unknown. epfl scis ‘ve now taken the 1st extensive look at a family of ~350 human proteins, showing t'they establish a complex interplay with transposable essentialisms 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 med.

the lab of didier trono at epfl revealed a few yrs ago dat a' protein serving as cofactor to many kzfps (krab-containing zinc-finger proteins) was involved in silencing transposable essentialisms during the 1st few dys of embryogenesis. now he and his collaborators ‘ve carried out an extensive analysis of human kzfps, retracing their evolutionary history and identifying their genomic targets.

the scis combined phylogenetics – the study of evolutionary relationships tween ≠ species, with genomics — the study of how the genome of an organism conditions its biology. by comparing the genomes of 203 vertebrates, they 1st traced the origin of kzfps back to a common ancestor of tetrapods (4-legged animals) and coelacanth, a fish that evolved over 400 million yrs ago. this evolutionary conservation of the kzfp-transposable element system hints to its primordial importance.

trono’s team then mapped out the genomic targets of most human kzfps, finding that the gr8est fraction recognizes transposable essentialisms. “the vast majority of kzfps binds to specific motifs in transposable essentialisms,” says trono. “for each kzfp we were able to assign one subset of transposable essentialisms, nolso found that one transposable element can often interact with several kzfps. tis a highly combinatorial and versatile system.”

the epfl scis finally went onna demonstrate that kzfps can convert transposable essentialisms in exquisitely fine-tuned regulatory platforms that influence the expression of genes, which likely takes place at all stages of development and in all human tissues.

“after emerging some 420 million yrs ago, kzfps evolved rapidly in a lineage-specific fashion, parallel to the invasion of host genomes by transposable essentialisms,” says trono. “this co-evolution resulted in shaping human gene regulatory networks tha're largely proper to our species or at least primate-restricted — the farther away in evolution, the fewer the similarities.”

the data from the study demonstrate that kzfp ptner up with transposable essentialisms to create wha’ the authors call “a largely species-restricted layer of epigenetic regulation”. epigenetics refers to biological processes — mostly biochemical modifications of the dna and its associated proteins — that condition the expression or repression of genes. as a field, epigenetics has come into prominence in recent yrs, revealing a previously unimagined complexity and elegance in genetics.

“kzfps contribute to make human biology unique,” says trono. “together with their genomic targets, they likely influence every single event in human physiology and pathology, and do so by bein’ largely species-specific — the general system exists in many vertebrates, but most of its components are ≠ in each case.” the findings of this work will help scis identify possible shortcomings of current animal models and construct a + accurate picture of how genes work in humans.

“this paper lifts the lid off something that had been largely unsuspected: the tremendous species-specific dimension of human gene regulation”, says trono. “t'has profound implications for our cogging of human development and physiology, and gives us a remarkable wealth of resrcs to examine how disturbances of this system mite result in diseases s'as cancer”.

src: epfl

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