Experts identify first non-coding RNA that controls chromosome loop formation

Recent research carried out by scientists from Massachusetts General Hospital (MGH) reveals that a significant player in the healthy development of female embryos also performs a vital role in controlling the behavior of chromosome loops and gene expression in both sexes.

The findings could help generate novel targets for drug development. The observations were published in the Cell journal.

Chromosomes are long, string-like structures composed of RNA, DNA, and proteins. A chromosome should fold into a loop to fit into the cell nucleus. These loops combine distant genetic material.

Genes and control elements—sequences that regulate genes—have to communicate with one another for the cell to work properly. Chromosome looping is kind of like bringing people together in a conference room so they can talk to one another.”

Jeannie Lee MD, PhD, Study Senior Author, Department of Molecular Biology, Massachusetts General Hospital

These interactions inside a chromosome loop control gene expression—a gene turned “on” to produce proteins or turned “off.” Chromosome loops are in continuous flux, growing and contracting as they alter their gene composition responding to environmental stimuli and the body’s developmental requirements. Returning to the metaphor of the conference room, a protein named CTCF performs as a door, describes Lee.

It was known earlier that a chromosome loop might have many sets of double doors—some closed, some open.

But what wasn’t known is how these doors open and close. Who are the gatekeepers?

Jeannie Lee MD, PhD, Study Senior Author, Department of Molecular Biology, Massachusetts General Hospital

The response was a surprise. Lee and fellow researchers identified that a form of RNA called Jpx is a gatekeeper that controls the behavior of CTCF in chromosome looping. Jpx RNA was not a stranger to Lee and her researchers.

Around eight years ago, they revealed that this noncoding form of RNA is a major player in the phenomenon called X chromosome inactivation, which is vital for normal development in all female mammals, including humans. Jpx RNA aids in counting X chromosomes in female cells very early in development. In case two are detected, one X chromosome is silenced or inactivated.

Lee’s team also included postdoctoral fellow Hyun Jung Oh, PhD, the study’s first author identified that Jpx RNA also determines in what combination the double doors are open at any specific time by “evicting” CTCF from the chromatin (a substance within a chromosome).

Jpx regulates whether multiple doors are open or just one, as well as which panels of double doors are open, left or right. By regulating that process, Jpx determines how big the chromatin loop is and, therefore, which genes around the loop are expressed.”

Jeannie Lee MD, PhD, Study Senior Author, Department of Molecular Biology, Massachusetts General Hospital

Jpx was the first form of RNA to be discovered as performing a major role in controlling the behavior of CTCF, however, there would be more, states Lee. According to her, that is exciting as there are probably 10 times more varieties of RNA than proteins.

While Jpx controls genes involved in the early development of an embryo, other RNAs anticipating identification might control the formation of chromosome loops that influence the risk for autoimmune disorders, cancer, and other diseases. Pinpointing these RNAs can boost the development of efficient new medications.

Source:
Journal reference:

Oh, H. J., et al. (2021) Jpx RNA regulates CTCF anchor site selection and formation of chromosome loops. Cell. doi.org/10.1016/j.cell.2021.11.012.

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