The human genome contains millions of sequences derived from so-called
transposable elements, genetic units that "jump" around the entire
genome. Long considered as junk DNA, transposable elements are now
recognized as influencing the expression of genes. However, the extent
of this regulation and how it is harnessed were so far unknown.
EPFL scientists have carried out a genomic and evolutionary 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
gene-regulatory networks that impact all of human biology, in both
health and disease.
‘Human proteins are responsible for harnessing the millions of transposable elements in the human genome.’
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, retracing 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
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 binds to specific motifs 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 versatile system."
The EPFL scientists finally went on to demonstrate that KZFPs can
convert transposable elements 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 years ago, KZFPs evolved rapidly in
a lineage-specific fashion, parallel to the invasion of host genomes by
transposable elements," says Trono. "This co-evolution resulted in
shaping human gene regulatory networks that are 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 partner up with
transposable elements to create what 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 years, revealing a previously unimagined complexity and elegance
"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 being largely
species-specific - the general system exists in many vertebrates, but
most of its components are different in each case." The findings of this
work will help scientists identify possible shortcomings of current
animal models and construct a more accurate picture of how genes work in
"This paper lifts the lid off something that had been largely
unsuspected: the tremendous species-specific dimension of human gene
regulation", says Trono. "It has profound implications for our
understanding of human development and physiology, and gives us a
remarkable wealth of resources to examine how disturbances of this
system might result in diseases such as cancer".