LEE LAB

Welcome to Jeannie Lee's lab at Massachusetts General Hospital. Our team of staff scientists, postdoctoral fellows, and PhD students are interested in understanding some of the fundamental differences between the sexes.  We use state-of-the-art technologies in molecular biology, biochemistry, cell biology, and embryology to understand how one X-chromosome is turned off in the female but not in the male.

Our lab studies how male (XY) and female (XX) cells use a mechanism called X-chromosome inactivation to achieve equality of sex chromosome gene expression. Our studies are focused on three noncoding RNA loci whose actions coordinate the many steps of X-chromosome inactivation. We are also interested in the mechanistic and evolutionary relationship between X inactivation and imprinting. Recent work by the Lee Lab suggests that imprinted X-chromosome inactivation is directly connected to meiotic sex chromosome inactivation in the male germline.

OUR WORK

In mammals, dosage compensation occurs by silencing on X-chromosome 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 imprined mechanism whereby the paternal X is always inactivated. Our laboratory is currently interested in how both forms are regulated and in the evolutionary connection between XCI and it's sister phenomenon, known as "autosomal imprinting."

Just as in autosomal imprinting, XCI is regulated by a master switch region that associates with non-coding RNA. The X-inactivation center (Xic) is about 100 kb and harbors three such non-coding RNA genes, including Xist, Tsix, and Xite. Chromosome-wide silencing requires Xist RNA, which spreads along the X and presumably recruits silencing factors to that chromosome. Xist is regulated in cis by its antisense partner, Tsix, which is responsible for keeping the X-chromosome inactive. Tsix is in turn regulated by Xite, an upstream locus harboring multiple intergenic transcripts and a Tsix-specific enhancer.

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?
4. What is the evolutionary relationship between XCI and genomic imprinting, and did imprinting evolve first on the X in mammals?