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Environmental Factor

Environmental Factor

Your Online Source for NIEHS News

October 2020

Falk lecture highlights critical X chromosome interplay in early life

Jeannie Lee shared her groundbreaking research into X-chromosome inactivation, a key process in female embryonic development.

Female mammals inherit two X chromosomes from each parent, whereas males inherit only one from the mother. To ensure a balanced distribution of X-linked genes in both sexes, each cell randomly turns off one of the X chromosomes in females during early embryonic development. That epigenetic process is called X-chromosome inactivation (XCI).

Scientists have long known about XCI and its association with X-linked disorders such as red-green color blindness and hemophilia. However, the exact biological mechanisms at play remained elusive for decades.

Jeannie Lee, M.D., Ph.D., professor of genetics at Harvard Medical School and Massachusetts General Hospital, has conducted trailblazing research into XCI. She shed light on some of her discoveries as part of the 2020 NIEHS Hans L. Falk Memorial Lecture on Sept. 8.

Jeannie Lee, M.D., Ph.D. Lee has published more than 100 papers on XCI and X-linked diseases in the past 20 years. (Photo courtesy of Jeannie Lee)

Unsolved mystery, until now

In 2006, Lee’s team showed that before XCI occurs, the two X chromosomes briefly touch at a spot known as the X inactivation center.

“This pairing is essential for the XCI to happen,” she said. “After being stuck for about 30 minutes, one of the chromosomes comes out as inactive while the other remains active. Nobody knew what the two chromosomes were saying to each other to make that decision until now.”

In a paper published Aug. 18 in Nature Cell Biology, Lee and her colleagues describe the role of critical RNAs and proteins that collaborate to make XCI happen.

Before pairing, the two X chromosomes express the same genes. Both also express two critical long noncoding RNAs called Xist and Tsix. Lee’s previous research established that Xist initiates XCI by recruiting inactivation factors and altering the 3D architecture of the X chromosome. In contrast, Tsix, by blocking Xist, prevents XCI.

3d illustration of chromosomes Lee has worked to uncover the mystery of XCI and develop potential therapeutic interventions for X-linked diseases.

The current study shows that an enzyme called DCP1A randomly binds to one of the X chromosomes and makes the Tsix RNA unstable. Another protein called CTCF — which acts as the inter-chromosomal glue — initially binds to the unstable form of Tsix. Through the action of DCP1A, the CTCF flips from binding Tsix RNA on the active X to binding the DNA on the future inactive X. This causes permanent shut down of Tsix, allowing Xist to turn on fully and complete the inactivation of that chromosome.

Benefits, drawbacks of genetic diversity

“Since not every cell turns off the same X chromosome, females are mosaic in their genetic makeup by virtue of having cells expressing X-linked genes of both the mother and father,” said Lee. “This provides females more genetic diversity and protection from X-linked diseases than males.”

For example, hemophilia, a blood clotting disorder, and autism, a developmental disorder, both disproportionately affect males. In females, mutations in the disease-causing genes of paternal X chromosomes can be compensated by healthy copies of the same genes in maternal X chromosomes.

Natalie Shaw, M.D. Shaw holds a secondary appointment in the NIEHS Reproductive and Developmental Biology Laboratory. (Photo courtesy of Steve McCaw)

Females also have the ability to produce a diverse immune response, which may explain why they tend to be better at fighting off infectious diseases than males.

“However, having a rich genetic abundance may act as double-edged sword for females,” Lee noted. “Since the female immune system is capable of recognizing more antigens than men, this also puts women at greater risk of developing autoimmune disorders,” she said.

“Research by Dr. Lee and her group has led to pioneering contributions in the field of X-linked diseases,” said Natalie Shaw, M.D., Lasker Clinical Research Scholar and head of the NIEHS Pediatric Neuroendocrinology Group in the Clinical Research Branch. She invited Lee to give this year’s Falk lecture.

Shaw collaborated with Lee on a paper published last year in the journal Genetics that examined the role of the SMCHD1 gene in XCI.

Citations:
Aeby E, Lee H, Lee Y, Kriz A, del Rosario BC, Oh HG, Boukhali M, Haas W, Lee JT. 2020. Decapping enzyme 1A breaks X-chromosome symmetry by controlling Tsix elongation and RNA turnover. Nat Cell Biol 22:1116–1129.

Wang C, Brand H, Shaw ND, Talkoowski ME, Lee JT. 2020. Role of the chromosome architectural factor SMCHD1 in X chromosome inactivation, gene regulation, and disease in humans. Genetics 213(2):685–703.

(Arif Rahman, Ph.D., is a visiting fellow in the National Toxicology Program Toxicoinformatics Group.)


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