PRC2, or polycomb repressive complex 2, is a key regulator of human development and controls gene expression patterns by altering the structure of chromatin, a complex formed by protein and DNA. As an enzyme complex, PRC2 modifies a protein in chromatin, resulting in key changes in chromatin structure that silence certain genes. Abnormal regulation of PRC2 function, often caused by mutations in the PRC2 gene, has been linked to cancers such as lymphoma, leukemia, brain tumors, and other diseases, including Weaver syndrome, a rare congenital disorder associated with rapid growth, skeletal abnormalities, and delayed development.
“Our findings bring us one step closer to understanding the chemistry of how PRC2 functions in normal cells and how mutations in the gene cause disease,” said senior author Dr. Xin Liu, Assistant Professor of Obstetrics and Gynecology, and of Biophysics at UT Southwestern.
The findings were published online Oct. 16 by the journal Science.
“Producing either too much or too little PRC2 enzyme can unexpectedly silence or activate genes, which is not good for the cell. This study revealed how a ‘normal’ level of PRC2 enzyme activity is kept and regulated in cells,” explained Dr. Liu, also a member of the Cecil H. and Ida Green Center for Reproductive Biology Sciences and the Harold C. Simmons Comprehensive Cancer Center, and a W.W. Caruth, Jr. Scholar in Biomedical Research.
Dr. Liu said the findings identify the various ways that PRC2 acts, which in turn is helpful in understanding the chemical basis of related diseases and should aid in the development of new treatments for those diseases.
“Indeed, several clinical trials are currently ongoing to target PRC2, and we believe our work will shed light on these and other studies in drug development by offering insights into how PRC2 works at the atomic level,” he said.
In particular, Dr. Liu indicated that small-molecule drugs are being developed to inhibit PRC2 enzyme activity for treatment of some types of lymphoma. These drugs may prove beneficial, he said, since PRC2 has been found to be overly active in promoting further development of these cancer types.
The findings lay the groundwork for further investigation of PRC2 function and regulation in both normal and diseased cells. Among next steps, the research team led by Dr. Liu is now elucidating how PRC2 is regulated during interactions with chromatin and how the complex interacts with other cellular proteins on and off chromatin. This work may offer a deeper and more thorough understanding of PRC2 function and its dysregulation in human disease.
From a science perspective, this finding is groundbreaking. The 4-year-long investigation – for the first time – revealed the 3-D atomic structure of PRC2, in this case from a fungus and at high resolution. Some molecules known to regulate the enzyme activity of PRC2 in both normal and cancer cells were captured in action in the structure as well. This work not only solved some long-standing mysteries about the molecular mechanisms of PRC2 enzyme catalysis and regulation, but also provided a structural framework for the development of future cancer therapies.
“The widely used analytic technique of X-ray crystallography was utilized to deduce the protein structures based on X-ray diffraction patterns of PRC2 crystals generated at synchrotron particle accelerators,” said Dr. Lianying Jiao, a postdoctoral researcher in the Liu lab and first author of the study.
The research was supported by grants from the Cancer Prevention and Research Institute of Texas, the Welch Foundation, the Rita Allen Foundation, and the National Institutes of Health. Dr. Liu also received support as a W.W. Caruth, Jr. Scholar in Biomedical Research at UT Southwestern, and from the Cecil H. and Ida Green Center Training Program in Reproductive Biology Sciences.
The study used resources of the Advanced Photon Source at Argonne National Laboratory and of the Advanced Light Source at Lawrence Berkeley National Laboratory, both supported by the U.S. Department of Energy Office of Science.
The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 45 NCI-designated Comprehensive Cancer Centers in the nation. The Simmons Cancer Center includes 13 major cancer care programs with a focus on treating the whole patient with innovative treatments, while fostering groundbreaking basic research that has the potential to improve patient care and prevention of cancer worldwide. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians.
The Simmons Cancer Center is among only 30 U.S. cancer research centers to be named a National Clinical Trials Network Lead Academic Participating Site, a prestigious new designation by the NCI, and the only cancer center in North Texas to be so designated. The designation and associated funding is designed to bolster the cancer center’s clinical cancer research for adults and to provide patients access to cancer research trials sponsored by the NCI, where promising new drugs often are tested.
About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to about 92,000 hospitalized patients and oversee approximately 2.1 million outpatient visits a year.
Media Contact: Debbie Bolles