About us
If you are passionate about RNA biology, epigenetics, and the 3D genome,
join us as we use X-Chromosome Inactivation to model the non-coding genome and discover its secrets.
join us as we use X-Chromosome Inactivation to model the non-coding genome and discover its secrets.
X-chromosome inactivation (XCI) is a biological process used by mammals like us to ensure that boys (XY) and girls (XX) have equal sex chromosome dosage despite having a different number of X-chromosomes. XCI happens very early during uterine development and leads to inactivation of one of the female embryo's 2 X-chromosomes. For XCI to occur, every embryo "counts" chromosomes. In embryos with 2 X's, one of the X's makes a "choice" to undergo inactivation. For this to happen properly, each X has to know what the other X intends to do. We believe that the X's communicate this choice through a "pairing" process in which they make contact briefly at two noncoding loci — Tsix/Xite and the telomere. The chosen X chromosome then initiates "silencing" within a specific region -- called the X-inactivation center"-- and silencing is "spread" throughout the large sex chromosome. During the silencing process, the X chromosome is folded like origami into a unique shape that helps to suppress gene activity. Thus, XCI involves a series of highly orchestrated steps. It is particularly interesting, because the major decision-makers (molecular regulators) appear to be non-coding in nature. Non-coding RNA plays a key role in every step of the XCI process, from counting to pairing to silencing and to 3D chromosome-folding. Our lab's goal is to understand how RNA interfaces with protein at each step of the XCI process.
We also aim to translate the knowledge gained from basic studies to treat human disorders — particularly neuro-developmental disorders and X-linked intellectual disabilities (XLID). Three disease areas of current interest are Rett Syndrome, the Fragile X Syndrome, and CDKL5 Syndrome. In each case, the girls and boys who suffer from the disorder harbor a perfectly good copy of the necessary gene, but the good copy is locked up by an epigenetic silencing mechanism: MECP2 in the case of Rett Syndrome, FMR1 for Fragile X, and CDKL5 for CDKL5 Syndrome. Our goal is to use our understanding of XCI to unlock the silent copy of each gene for therapeutic benefit.
We also aim to translate the knowledge gained from basic studies to treat human disorders — particularly neuro-developmental disorders and X-linked intellectual disabilities (XLID). Three disease areas of current interest are Rett Syndrome, the Fragile X Syndrome, and CDKL5 Syndrome. In each case, the girls and boys who suffer from the disorder harbor a perfectly good copy of the necessary gene, but the good copy is locked up by an epigenetic silencing mechanism: MECP2 in the case of Rett Syndrome, FMR1 for Fragile X, and CDKL5 for CDKL5 Syndrome. Our goal is to use our understanding of XCI to unlock the silent copy of each gene for therapeutic benefit.
Molecular events at the initiation of XCI. Co-transcriptional recruitment of Polycomb repressive complex 2 (PRC2) and tethering to YY1 explain the cis-acting nature of Xist. First, the biallelic Xist antisense gene (Tsix) prevents initiation of X‑chromosome inactivation (XCI) (step 1). Xist expression is then permitted during cell differentiation by induction of the Jpx activator and monoallelic loss of Tsix on the future (denoted with an asterisk) Xi following X–X pairing (step 2). Xist then co-transcriptionally recruits PRC2. YY1 binds the Xi ‘nucleation centre’, but is blocked from binding the active X chromosome (Xa) (step 3). The Xist–PRC2 complex co-transcriptionally loads onto the nucleation center (step 4) and spreads across the X chromosome (step 5). RNAPII, RNA polymerase II. From Lee, 2011, NatRevMCB 12, 815.
Our lab is jointly appointed through the Department of Genetics, The Blavatnik Institute of Harvard Medical School, and the Department of Molecular Biology, Massachusetts General Hospital. We are located in the Simches Research Building in the main campus of the MGH, within the Beacon Hill neighborhood — home to many of the city's finest shops and restaurants and within walking distance and a short transit of the area's major academic institutions, research centers, and biotech companies.