Jeanne Lawrence, Ph.D.

Principal Investigator

 

Lisa Hall, Ph.D.

Research Assistant Professor

 

Christine Clemson, Ph.D.

Postdoc

Gayle Pageau

MD/PhD Student

 

John McNeil

Research Engineer

 

Meg Byron

Research Associate

 

John Butler

Research Associate

 

Laurie Lizotte

Lab Coordinator

 

 

 

 

 

 

 




Research interests of the lab bridge the study of nuclear structure with human genome organization and function, in both normal cells and in specific human genetic diseases. A major focus is the localization and functional organization of specific genes and their cognate mRNAs within the mammalian nucleus. In recent years it has become increasingly appreciated that the nucleus contains a number of non-chromatin “compartments”, enriched in different subsets of RNA metabolic factors. Some of these nuclear structures or bodies are known to be involved in genetic diseases or specific cancers. We are studying the structural and functional relationship of different intranuclear structures to individual genes and RNAs, in normal and disease states, to elucidate their respective roles in gene expression and RNA metabolism. Thus far this work has demonstrated that there is a locus-specific organization of genomic DNA with respect to distinct nuclear compartments, that is related to specific gene expression. We are currently extending these studies to include an analysis of transgenes and patient mutations in disease. For example, we are studying the impact of splice-junction defects in Osteogenesis Imperfecta and triplet repeat expansion in myotonic dystrophy, to understand the inter-relationship of nuclear RNA metabolism with nuclear structure in disease pathogenesis.

The second major focus of the lab is on the inactivation of the mammalian X-chromosome, and in particular the relationship of XIST RNA to X inactivation. The XIST gene was identified in other labs as a potential key to the X-inactivation process, however the RNA was found to encode no open-reading frame. Our laboratory, using an innovative molecular cytological approach, discovered that the XIST gene produces a stable 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 establishes a precedent for a new type of functional nuclear RNA involved in chromatin regulation. Our studies now focus on investigating how this novel RNA binds to and inactivates an entire X chromosome, studying X;autosome translocations in patient cells as well as XIST transgenes inserted into autosomes of cells in different states of developmental competence. Recent work indicates that XIST RNA’s relationship to the chromosome exhibits sequence specificity.

 








2008
John Butler / John.Butler@umassmed.edu