The Lawrence Lab
The lab’s research bridges fundamental questions about genome regulation with pursuing the clinical implications of recent advances in our studies of epigenetics. The genome is not a linear entity, but exists as a complex three-dimensional structure within a highly complex nuclear structure. A major focus of the lab has been to demonstrate and investigate the functional organization of specific human genes and their cognate mRNAs within a highly compartmentalized nuclear structure. In recent years it has become increasingly well appreciated that the nucleus contains a number of non-chromatin “compartments”, enriched in different subsets of RNA metabolic factors. Our lab has demonstrated that there is a locus-specific organization of genomic DNA with respect to distinct nuclear compartments, which relates and contributes to gene regulation. Some nuclear structures or bodies, including the specific heterochromatic structures, are involved in genetic diseases. Examples studied in our lab include toxic repeat nuclear RNA foci in myotonic dystrophy or epigenetic defects of heterochromatin in FSH muscular dystrophy. Most recently our work has come to focus most heavily on epigenetic changes to nuclear structure and heterochromatin in human pluripotent stem cells (iPS cells) and in cancer cells or tumors.
A pre-eminent model for early embryonic regulation by heterochromatin formation is the inactivation of the human X-chromosome, where epigenetic changes are manifest cytologically across an entire chromosome. Our lab is at the forefront of investigating how a large non-coding RNA can control this whole process. The XIST gene was identified in other labs as a potential key to the X-inactivation process, however the RNA did not encode an open-reading frame. Using powerful molecular cytology approaches developed in our lab, we were able to demonstrate that the XIST gene produced a stable, functional nuclear RNA that actually “paints” the entire inactive X-chromosome, but not the active X chromosome. Spreading of XIST RNA across the chromosome is the first step in transforming it into a heterochromatic state. This established the precedent for a new type of functional nuclear RNA involved in chromatin regulation, and other large non-coding RNAs are also being examined in our lab. Current studies focus on how XIST RNA interacts with the chromosome, and what DNA sequences and chromosomal proteins impact this process, using XIST transgenics and bioinformatics as well as cytological epigenetics. We are currently also pursuing a novel translational approache for gene therapy that stems from these advances in understanding non-coding RNA and chromosome regulation.