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Principal Investigator |
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Research Assistant Professor |
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Postdoc |
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MD/PhD Student |
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Research Engineer |
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Research Associate |
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Research Associate |
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Lab Coordinator |
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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.
