When
an embryo is formed, its genes – donated by a fertilising sperm and egg
– are silent. Somehow, at an early stage of development, embryo genes
must be switched on. Without this vital 'genes on' switch in the embryo,
none of us would be here, yet surprisingly little is known about what
the switch looks like, or the identity of the 'molecular finger' that
pushes the switch.
Thanks to research published today in Cell Reports, however, embryologists have now described the switch and can reveal the identity of the finger that pushes it.
The
team made their discovery in mice by combining a state-of-the-art
method to inject sperm into eggs with the latest techniques in messenger
RNA (mRNA) sequencing.
mRNA
is the genetic ‘middleman’ that reads information from genes and
delivers it to regions in the cell where proteins (the building blocks
of life) are made. mRNA is produced in eggs before fertilisation but
also in embryos when the genome has been switched on: the researchers
were able to differentiate between the two types and to characterise the
embryo 'on' switch.
Their
approach identified gene activity at precise times after fertilisation
in new embryos. It was found that in mouse embryos, the activity kicks
off within four hours of sperm injection and follows a programme: the
genes aren’t switched on willy-nilly, but in a pre-set order.
The
team identified the sequence of gene activation in this pre-set order
in one-cell embryos for the first time in any species – and showed that
the functions of the active genes fit with features of early embryo
development.
Scientists
have previously worked out in many cases which 'molecular fingers'
switch on which genes, and because of this, the authors of the new study
were able to predict which fingers were responsible at the start of
embryonic development: the fingerprints of some were on the embryo
genes, allowing the culprit fingers to be identified.
In an extraordinary turn, this detective work showed that many of the trigger suspects are also associated with cancer.
"Many
factors responsible for the dawn of gene activity in embryos have long
been known to be major oncogenes," said the research lead and the senior
author and added: "Quite possibly, carcinogenesis recapitulates
embryogenesis."
The
team followed up on its detective work by showing that the suspected
factors ('molecular fingers') are indeed present in one-cell embryos,
which inherit them from eggs. When they prevented the factors from
working by applying inhibitors that block their activity after
fertilisation, the embryos stopped developing almost immediately.
The
researchers went further for one molecular finger – a cancer-associated
factor called c-Myc. If c-Myc were actually responsible for switching
on genes at the start of development, the group reasoned that inhibiting
it should prevent the switch. That is exactly what they found: without
c-Myc activity, many of the genes were not switched on, indicating that
c-Myc is indeed a molecular finger that switches on embryo genes.
The
group suggests c-Myc and other factors are dormant in eggs until they
are themselves activated by fertilisation. This work on mice overlaps
with findings published recently by the researchers showing gene
activity in human embryos also starts at the one-cell stage.
"Many
genes switched on from the get-go in mouse and human one-cell embryos
are counterparts," said the first author. "The involvement of the same
oncogenic transcription factors is predicted in both species."
It
therefore appears that this study’s findings not only illuminate the
mechanisms that regulate the start of mammalian development but also
promise to set the scene for game-changing insights into processes that
trigger cancer, which in the majority of cases are elusive and remain
unknown.
"Our
work could open a new clinical chapter for the early detection of
cancer," said the senior author and added that he hoped to follow the
leads provided by the team's detective work so that parallels between
embryos and cancer could in the future be exploited to close gaps in our
understanding of both.
https://www.cell.com/cell-reports/fulltext/S2211-1247(23)00034-7
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fa-program-of-successive&filter=22