An important player in the healthy development of female embryos is also proving to play a key role in regulating the behavior of chromosomal loops and gene expression in both sexes, according to a new study by researchers at Massachusetts General Hospital (MGH). These findings, reported in the journal Cell, could help create new targets for drug development.
Chromosomes are long, string-like structures made up of DNA, RNA, and proteins. A chromosome must fold in a loop to fit into the nucleus of a cell. These loops bring together distant genetic material. “Genes and control elements – sequences that regulate genes – need to communicate with each other for the cell to function properly,” says Jeannie Lee, MD, PhD of the Department of Molecular Biology at MGH. looping is a way to bring people together in a conference room so they can talk to each other. ”
These interactions within a chromosomal loop regulate the expression of the gene, ie whether a gene is “activated” and thus produces protein or “deactivated”. Chromosomal loops are constantly flowing, growing and contracting as their gene composition changes in response to environmental stimuli and the body’s developmental needs. Going back to the conference room metaphor, a protein called CTCF acts like a door, Lee explains, and it was already known that a chromosomal loop can have several sets of double doors – some open, some closed. “But what was not known was how these doors open and close,” Lee explains. – Who are the guards?
The answer turned out to be a surprise. Lee and her team discovered that a form of RNA known as Jpx is a guardian that regulates CTCF behavior in the chromosomal loop. Jpx RNA was no stranger to Lee and her fellow investigators. Eight years ago, they showed that this uncoded form of RNA is a key player in the phenomenon known as X chromosome inactivation, which is essential for the normal development of all female mammals, including humans. Jpx RNA helps count X chromosomes in very early developing female cells; if two are detected, one X chromosome is inactivated or silenced.
However, Lee’s group, which included postdoctoral fellow Hyun Jung Oh, PhD, the first author of the study, found that Jpx RNA also determines what combination of double doors are open at a time, “avoiding ”CTCF from chromatin (a substance on a chromosome). “Jpx regulates whether multiple doors are open or just one, and which double door panels are open, left or right,” says Lee. “By regulating this process, Jpx determines how large the chromatin loop is and therefore which genes around the loop are expressed.”
Jpx is the first form of RNA that has been identified as having a vital role in regulating CTCF behavior, but there will be many more, Lee predicts. It’s exciting, she says, because there are probably 10 times more varieties of RNA than proteins. While Jpx regulates the genes involved in the early development of an embryo, other RNAs awaiting discovery may regulate the formation of chromosomal loops that influence the risk of cancer, autoimmune disorders and other diseases, says Lee. The identification of these RNAs could accelerate the development of new effective drugs.
Materials provided by Massachusetts General Hospital. Note: Content can be edited for style and length.