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RESEARCH TEAM IDENTIFIES MECHANISM RESPONSIBLE FOR UNIQUE GENOME STRUCTURES IN DIFFERENT CELLS
Protein complexes responsible for genome structure linked to developmental diseases
August 20, 2010
WORCESTER, Mass. — A team of researchers from the University of Massachusetts Medical School, the Whitehead Institute, Massachusetts Institute of Technology and the University of Colorado has discovered a new mechanism responsible for controlling genomic structure and activating genes to generate differentiated cell types.
Though each cell contains a person’s entire genome, which genes are expressed in the cell help determine whether it becomes a skin cell, nerve cell or muscle cell. The exact mechanism that determines which genes in a cell are expressed and how they are turned on is only partially understood. The team’s research, published online in Nature this week, details how a DNA loop formed at the beginning of cell-specific genes enables activation of these genes, thus leading to the formation of different cell types. For activation, regulatory factors and gene expression machinery bound to two different parts of the DNA–called the promoter and the enhancer–must come into contact. This contact, facilitated by the protein complexes Mediators and Cohesin, form a DNA loop that is specific to each cell type.
Experiments performed by Ye Zhan, a research associate in the lab of Job Dekker, PhD, associate professor of biochemistry & molecular pharmacology, helped lead to the identification of these loops. Employing chromosome conformation capture (3C) technology developed by Dr. Dekker, Zhan established that Mediator and Cohesin are involved in building chromatin loops that bring gene promoters in close spatial proximity to their regulatory elements–leading to gene activation.
“This work highlights the biological importance of the three-dimensional organization of genes inside cells,” said Dekker. “Cohesin and Mediator are critical determinants of this organization.”
Problems with the DNA loop structure can interfere with activation of cell-specific genes, causing the cell to lose its normal state. Mutations in Cohesin and Mediator can lead to developmental syndromes and diseases including Opitz-Kaveggia syndrome, Lujan syndrome, schizophrenia and Cornelia de Lange syndrome, and could be caused by a defect in loop formation between sets of genes and their regulatory elements.
About the University of Massachusetts Medical School
The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $240 million in research funding annually, 80 percent of which comes from federal funding sources. The mission of the Medical School is to advance the health and well-being of the people of the commonwealth and the world through pioneering education, research, public service and health care delivery with its clinical partner, UMass Memorial Health Care. For more information, visit www.umassmed.edu.