Developmental Biology - Transposons|
Taming 'Jumping' Genes
Transposable elements regulate the rate at which DNA is transcribed into RNA...
The human genome is fascinating. Once predicted to contain about a hundred thousand protein-coding genes, it now seems that the number is closer to twenty thousand, or maybe less. And although our genome is made up of about three billion units - "base pairs" - many of these don't seem to belong to specific genes. For that reason, they were delegated to the dustbin of genetics: literally being called "junk DNA".
It turns out, junk DNA is actually critical to coordinating and regulating our 20,000 or so genes. For example, sequences of DNA that "jump" around our genome influencing how our 20,000 regular genes function.
Jumping DNA are "transposable elements" or transposons, of DNA and are estimated to number over 4.5 million within a single individual's genome.
Transposons frequently contain binding sites for transcription factors - proteins that regulate the rate at which DNA is transcribed into RNA, the first step of gene expression. By moving around the entire genome, Transposons renew the pool of binding sites enabling transcription factors, thus becoming "motors" for genomic evolution.
But at the same time, transposable elements can also be very dangerous. They are genotoxic, meaning they can cause mutations which incapacitate genes — and disruption of gene activity can lead to severe diseases or even death.
A question at large is, how can the genotoxic potential of transposons be kept in check without compromising their regulation of the genome?
Scientists from the lab of Didier Trono at EPFL found a family of proteins known as KZFP (for Krüppel-associated box-containing zinc finger proteins), act as "key facilitators" by domesticating regulatory sequences embedded in transposons themselves. The research is published in Cell: Stem Cell.
Shortly after the egg is fertilized by the sperm, transposons are among the first gene sequences to function. Researchers found KZFPs quickly "tame" transposons in order to minimize their impact on the earliest stages of embryo organization. This allows transposons to be used later in development as well as in adult tissues. In this way, KZFPs play a key role in how the human genome is regulated — by helping incorporate transposon-based control sequences into transcription networks.
"Our results reveal how a family of proteins, long considered an oddity of nature, turn foes into friends. They show KZFPs do not just sentence transposons to perpetual silence, but domesticate their regulatory potential for the benefit of our genome.
Our findings also imply anomalies in the completion of this process fatally compromise the earliest phases of human embryo development."
Didier Trono PhD, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
• KLFs foster EGA by activating enhancers embedded in young TEs (TEENhancers)
• TEENhancers confer a degree of species specificity to early genome activation
• TEENhancers stimulate the expression of KZFPs responsible for their repression
• These KZFPs in turn facilitate TEENhancers’ exaptation as tissue-specific regulators
Expansion of transposable elements (TEs) coincides with evolutionary shifts in gene expression. TEs frequently harbor binding sites for transcriptional regulators, thus enabling coordinated genome-wide activation of species- and context-specific gene expression programs, but such regulation must be balanced against their genotoxic potential. Here, we show that Krüppel-associated box (KRAB)-containing zinc finger proteins (KZFPs) control the timely and pleiotropic activation of TE-derived transcriptional cis regulators during early embryogenesis. Evolutionarily recent SVA, HERVK, and HERVH TE subgroups contribute significantly to chromatin opening during human embryonic genome activation and are KLF-stimulated enhancers in naive human embryonic stem cells (hESCs). KZFPs of corresponding evolutionary ages are simultaneously induced and repress the transcriptional activity of these TEs. Finally, the same KZFP-controlled TE-based enhancers later serve as developmental and tissue-specific enhancers. Thus, by controlling the transcriptional impact of TEs during embryogenesis, KZFPs facilitate their genome-wide incorporation into transcriptional networks, thereby contributing to human genome regulation.
Julien Pontis, Evarist Planet, Sandra Offner, Priscilla Turelli, Julien Duc, Alexandre Coudray
Thorold W. Theunissen, Rudolf Jaenisch and Didier Trono.
Whitehead Institute for Biomedical Research
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Apr 24 2019 Fetal Timeline Maternal Timeline News
New research reveals how KLF4 and KLF17 are the main drivers of human pre-implantation gene transcription, by activating transposon (transposable elements or TEs) enhancers. CREDIT: EPFL.