Non-coding RNA plays a significant role in the regulation of chromosome loop behavior and gene expression

A crucial player in the healthy development of female embryos has been found to play an important role in regulating the behavior of chromosome loops and gene expression in both sexes, according to a new study conducted by researchers at Massachusetts General Hospital (MGH). These findings, reported in the journal Cell may help in the creation of new targets for drug development.

Chromosomes are string-like structures made up of DNA, RNA and proteins. A chromosome has to fold into a loop to fit into the nucleus of cells. The loops connect distant genetic material.

In order for cells to function properly, control elements and genes must communicate with one to communicate with one another. Chromosome looping can be described as like bringing people together in the conference room so that they can talk to one another.”

Jeannie Lee, MD, PhD, Senior Author, Department of Molecular Biology, MGH

These interactions within a Chromosome Loop regulate gene expression. This is how a gene can be turned “on” to produce proteins or “off”. The chromosome loops are constantly changing. They alter the genes’ composition when they respond to environmental stimuli. Lee explains that CTCF, also called CTCF, acts as an entrance. It was previously known that a chromosome loop can have multiple sets or double doors, some of which are open and some shut. Lee clarifies that it was not understood how these doors open or close. “Who are the gatekeepers?”

The answer came as surprising. Lee and her team have discovered that a type of RNA called Jpx is an important gatekeeper that regulates the behavior of CTCF in chromosome looping. Lee and her coworkers were familiar with Jpx RNA. They discovered that the noncoding form RNA was a key player in the phenomenon of X chromosome activation eight years ago. This is crucial for normal development in all mammals including humans. JpxRNA is used to count Xchromosomes within female cells at the beginning of development. If two are identified the Xchromosome that is one of them will be inactivated or silenced.

Lee’s research team, which included Hyun Jung Oh, PhD, a postdoctoral fellow, discovered that JpxRNA also decides the double doors’ combination that is open at any time by “evicting CTCF” from the chromatin, a substance within achromosome. “Jpx regulates whether multiple doors are open or only one, and which double doors are open, right or left,” says Lee. “By regulating that process, Jpx determines how big the chromatin loop is, and the consequently which genes within the loop are expressed.”

Lee predicts that Jpx is the very first form to be recognized as having a crucial role in the regulation of CTCF behavior. But there will be many more, Lee says. She believes this is exciting as there are 10 times more RNA varieties than proteins. Lee says that Jpx regulates genes involved in the development of the embryo, but other RNAs are still being discovered and could influence the development of chromosome loops which can have an impact on the risk of developing cancer, autoimmune disorders or other illnesses. These RNAs could be identified and utilized to create new, effective treatments.

Lee is also the director of The Lee Laboratory and a professor at Harvard Medical School of Genetics.

This research was made possible through grants from the National Institutes of Health and the Howard Hughes Medical Institute.

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