In mammals, dosage compensation occurs by silencing one of the X-chromosomes in female cells, a process known as X-chromosome inactivation (XCI). Two types of XCI have been described in mice: a random mechanism in which either the maternal or paternal X can be inactivated, and an imprinted mechanism whereby the paternal X is always inactivated. The Lee lab is currently interested in how both forms are regulated and in the evolutionary connection between XCI and its sister phenomenon, known as “autosomal imprinting.” Ongoing work in the lab addresses a number of questions, including: 1) How do the three non-coding loci interact with each other at the chromatin and RNA levels to bring out the various steps of XCI, including epigenetic choice and gene silencing? 2) How does X-chromosome counting take place? 3) What is the chromatin structure at the X-inactivation center and how does this relate to the XCI mechanism? and 4) What is the evolutionary relationship between XCI and genomic imprinting, and did imprinting evolve first on the X in mammals?
As an Innovation Fund investigator, Lee’s lab is collaborating with the lab of Raymond J. Kelleher III, M.D., Ph.D. to combine an expertise in genetics and X-chromosome inactivation with that of neuroscience. Female mammals inherit two X chromosomes, one from each parent, while males inherit only one. In order to ensure that males and females have an equal amount of X chromosome gene expression, females silence the genes on one X chromosome in a process known as X chromosome inactivation (XCI). XCI results in the random inactivation of maternal X chromosomes in some cells and paternal X chromosomes in others. Notably, cellular differences are exhibited depending on whether a cell expresses the male- or female-inherited X chromosome. In females with Turner syndrome, cells carry only one copy of the X chromosome, either from the mother or the father. Together, Lee and Kelleher will utilize mouse models of Turner syndrome to investigate how the maternal or paternal origin of the X chromosome affects behavior, such as learning, memory, and social interactions. They will compare the difference in gene expression between the maternal X chromosome and the paternal X chromosome to understand how girls with Turner syndrome exhibit different symptoms. This work could provide insights into sex-specific differences in diseases associated with inheritance of the X chromosome and neurological diseases like autism, and could have major psychosocial, clinical, and societal impacts.