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RNA Play a Vital Role in Gene Activity

e finding marks the first time that ncRNA has been shown to affect gene expression on a chromosome other than its own.

The researchers believe that HOTAIR functions by affecting chromosomal packing in the nucleus. Inactive chromosomal regions are tightly wound around proteins called histones and cannot be copied into RNA. Loss of HOTAIR in skin cells specifically frees the HOXD control region for binding by activating proteins.

"Next we need to find out how these RNAs work structurally," said Rinn, "and what upstream regulatory molecules might be controlling their expression." They have one clue: HOTAIR binds to and activates a group of enzymes called the Polycomb Repressive Complex 2 that modifies histones and helps them wind up the DNA.

The researchers' interest is more than just theoretical. Polycomb proteins are improperly regulated in some types of cancers. HOX gene expression patterns are likely important to keep stem cells from improperly differentiating into skin, muscle, or other tissues. Understanding how ncRNAs affect these processes will have important implications for cancer therapies and stem cell research, they believe.

"We are really interested in how ncRNA finds its putative target in the genome," said Chang. "There remains a whole level of biological complexity to be explored, including how HOTAIR knows where to go, how it talks to other factors and how it controls histones."

The work will also provide insight into the evolution of gene regulation. Because RNA is thought to have preceded DNA in the evolutionary timeline, it makes sense that it still plays a role in controlling DNA's function.

Rinn and Chang's Stanford collaborators on the research include cancer biology graduate students Jordon Wang and Xiao Xu; surgical postdoctoral scholar Samantha Brugmann, PhD; research assistant Henry Goodnough; and Jill Helms, PhD, associate professor of surgery. Non-Stanford
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