Deleting a gene in mouse embryos caused cardiac defects and early death, leading researchers to identify a mechanism that turns developmental genes off and on as an embryo matures, a team led by a scientist at The University of Texas M. D. Anderson Cancer Center reported today in Molecular Cell.
"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," said senior author Edward T.H. Yeh, M.D., professor and chair of M. D. Anderson's Department of Cardiology. "This novel pathway marks an advance in our understanding of how developmental genes are turned on and off."
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," Yeh said, "and how epigenetics and development are unexpectedly tied together by the SUMO/SENP2 system."
The key actors are members of two tightly associated families of proteins that Yeh and colleagues discovered and continue to study. 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).
This line of research started when Yeh and colleagues knocked 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:
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," Yeh said. 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.
"By understanding how development unfolds, we can better control this process, which includes cell proliferation and organ development," Yeh said. "This will help us to better understand cancer.
"SUMO and SENP are important in cancer development, neurological diseases and heart development. Everything under the sun can be regulated by this system," Yeh said. "Here we've established a new role for SUMOylation, mediating the interaction between protein and protein methylation in epigenetic regulation."
Funding for this research was provided by from the National Natural Science Foundation of China, National Basic Research Program of China and grants from the U.S. National Cancer Institute. Yeh also is the McNair Scholar of the Texas Heart Institute/St. Luke's Episcopal Hospital.
Co-authors with Yeh are co-first author Yitao Qi, Ph.D., and Robert Schwartz, Ph.D., both of the Texas Heart Institute/St. Luke's Episcopal Hospital, and co-first author Xunlei Kang, M.D., Ph.D., Yong Zuo, Ph.D., Qi Wang, Yanqiong Zou and Jinke Cheng, D.V.M., all of the Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine in Shanghai.
About M. D. Anderson
The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For six of the past eight years, including 2009, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.
Scott Merville | EurekAlert!
Kidney tumor: Genetic trigger discovered
18.06.2018 | Julius-Maximilians-Universität Würzburg
New type of photosynthesis discovered
18.06.2018 | Imperial College London
Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.
Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...
The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.
Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.
An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.
Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...
Light detection and control lies at the heart of many modern device applications, such as smartphone cameras. Using graphene as a light-sensitive material for...
Water molecules exist in two different forms with almost identical physical properties. For the first time, researchers have succeeded in separating the two forms to show that they can exhibit different chemical reactivities. These results were reported by researchers from the University of Basel and their colleagues in Hamburg in the scientific journal Nature Communications.
From a chemical perspective, water is a molecule in which a single oxygen atom is linked to two hydrogen atoms. It is less well known that water exists in two...
13.06.2018 | Event News
08.06.2018 | Event News
05.06.2018 | Event News
18.06.2018 | Earth Sciences
18.06.2018 | Process Engineering
18.06.2018 | Life Sciences