A mechanism that turns developmental genes off and on as an embryo matures has been identified by researchers.
Dr. Edward T.H. Yeh at The University of Texas M. D. Anderson Cancer Center could make the above discovery after he deleted a gene in mouse embryos and saw it causing cardiac defects and early death.
Advertisement"Our study focused on regulation of two genes that are critical to the healthy development of the heart, but many other genes are regulated in this way. This novel pathway marks an advance in our understanding of how developmental genes are turned on and off," said Yeh.
All cells in an embryo contain the same DNA. Different genes are turned off and on in different cells at different times to form specific tissues and organs as the embryo develops.
This gene regulation is accomplished by epigenetic processes that control gene expression without altering DNA.
Instead, epigenetic processes attach chemical groups to genes or to histones, proteins that are intertwined with DNA to form chromosomes, to activate genes or to shut them down.
"Our findings provide a new window through which to look at epigenetic control and how epigenetics and development are unexpectedly tied together by the SUMO/SENP2 system," said Yeh.
The key actors are members of two tightly associated families of proteins-the first, Small Ubiquitin-related Modifier, or SUMO, attaches to other proteins to modify their function or physically move them within the cell (SUMOylation).
The second, Sentrin/SUMO-specific protease 2, or SENP2, snips SUMO off of proteins (de-SUMOylation).
The researchers held on to this line of research after knocking SENP2 out of mouse DNA and found that the embryos died at about day 10.
Their hearts had smaller chambers and thinner walls.
Through a series of experiments, the team worked backward from this observation to show that a group of proteins called the polycomb repressive complex 1 (PRC1) that silences genes must first bind to a particular methylated address on a histone and,
A key component of the complex must be SUMOylated to make this connection, which results in the silencing of Gata4 and Gata6, genes that are essential for cardiac development.
In early development, SENP2 works as a switch to turn on Gata4 and Gata6.
"When SENP2 is turned on, it peels SUMO off of PRC1, which then falls off the histone, and when that happens, the lock is removed and genes are transcribed," said Yeh.
Gata4 and Gata6 are free to properly develop the heart.
In short, SUMO helps the PRC1 complex repress genes, and SENP2 reverses this repression, allowing gene transcription and expression.
The study has been reported in Molecular Cell.
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