Genetics, Molecular Biology
Massachusetts General Hospital
Dr. Lee is also a professor of genetics and pathology at Harvard Medical School and a molecular biologist at Massachusetts General Hospital, Boston.
Jeannie Lee studies how male (XY) and female (XX) cells use a mechanism called X-chromosome inactivation to achieve equality of sex chromosome gene expression. Her studies are focused on three noncoding RNA loci whose actions coordinate the many steps of X-chromosome inactivation. She is also interested in the mechanistic and evolutionary relationship between X inactivation and imprinting. Her recent work suggests that imprinted X-chromosome inactivation is directly connected to meiotic sex chromosome inactivation in the male germline.
Women and men have many apparent physical differences. But one less well-known distinction is more covert, occurring inside every cell of a woman’s body. During embryonic development, a female becomes a genetic mosaic by randomly inactivating one of two X chromosomes in the cells of her body.
Females close down an X chromosome to be equal to males, who as XY have only one X chromosome in their cells. Evolution has determined that a double dosage of most of the 1,000 or so genes on the X chromosome in cells is bad for female humans and other species. Hence, the female embryo stops expression of the vast majority of the genes on one of the two X chromosomes.
Dissecting the molecular mechanisms behind X inactivation is Jeannie Lee's research focus. While much remains to be discovered, Lee has identified key genes in the mouse responsible for X inactivation and has revealed how X chromosomes behave to shut one of their sisters down.
Lee says she is particularly interested in X inactivation because it is an example of a biological phenomenon called epigenetics, the study of inherited changes in gene activity that do not involve alterations in the primary sequence of DNA.
In women, the DNA is essentially the same on both the X chromosomes—except one is from mom and one is from dad, Lee explains. But a physical process shuts down most of the gene activity on one of the X chromosomes. Related processes may be occurring during embryo development to enable the cells in the body to perform different functions. Although all cells have the same genetic makeup, different genes are turned on or off inside them, depending on the cell type. The turning-off mechanism is epigenetic.
Lee first became interested in gene expression and epigenetics as a Harvard undergraduate doing research. "I was introduced to noncoding RNA and jumping genes and the incredibly plastic genome and its various modifications," Lee says. (Jumping genes are DNA sequences that move within the genome; they are not epigenetic, per se, because the sequence changes. Noncoding RNAs do not get translated into proteins but instead perform regulatory functions in an epigenetic fashion.)
Lee then pursued an M.D./Ph.D. at the University of Pennsylvania. She eventually opted for the laboratory, not the clinic, and pursued medical research because of its potential to help people, she says. For her Ph.D., she studied the genetics of fragile X syndrome, the most common cause of inherited mental impairment due to an epigenetic alteration on the X chromosome. When the fragile X mutation is passed through the mother's X chromosome, not the father's X, a son will get the disease.
To gain experience with mouse models of disease, in 1995 Lee became a postdoctoral fellow in the Massachusetts Institute of Technology laboratory of transgenic science pioneer Rudolf Jaenisch. Transgenics is the genetic engineering of an animal to produce a model of human disease.
Jaenisch was also studying epigenetics. While there, Lee delved into X inactivation. It was known then that there is a gene involved in X inactivation called Xist, which is a noncoding RNA on the X chromosome. It was identified in 1991. It was unknown if other genes play a role. Lee aimed to find out.
She took a piece of DNA surrounding the Xist gene and put it into the non-sex chromosomes of mouse cells growing in culture. She found that the DNA caused the chromosomes to undergo inactivation, which they normally do not experience.
She then became an independent investigator at Massachusetts General Hospital, where she winnowed the DNA piece to reveal other genes required for inactivation. One gene she discovered, which she calledTsix, is another noncoding RNA that regulates Xist and has the reverse DNA sequence of Xist.
Her findings revealed that X inactivation essentially is regulated by noncoding RNAs, explains Lee, who adds that similar mechanisms could be involved in other areas of gene regulation. "Until recently, scientists underestimated noncoding RNA's role in controlling gene expression, but they are now studying noncoding RNA's action in many cell types and diseases," she says.
Recently, Lee discovered another fascinating activity of X chromosomes during inactivation: They align in pairs before "deciding" which one will become inactivated. "The finding was striking because mammalian chromosomes do not pair in cells in the body," Lee explains. In sperm and egg cells during meiosis, chromosomes pair and segregate into appropriate daughter cells but not in the cells of the body.
Lee continues to study X-inactivation genes and is trying to decipher the molecular communication occurring between the X chromosomes as they randomly shut one off. She also is studying how X inactivation passes down through the generations.
As a young person, Lee never imagined her current life as scientist, thinking her love for science would lead her to medicine. But she was drawn to research because she felt that studying the biological processes of health and disease ultimately would impact more people. She remains committed in her work to apply scientific principles to better understand some fundamental differences between women and men and how genes are controlled in the body.