Research in the lab
Our work focuses on the formation and regulation of
chromatin domains and their ultimate roles in epigenetic genome regulation. We
are particularly interested in the mechanisms of heterochromatin establishment
and function. Heterochromatin operates in organisms from yeast to humans to
determine cell identity and maintain genome stability by silencing genes.
Because heterochromatin functions in such central processes, misregulation of
this genomic structure can have dire consequences such as cancer or abnormal
development. Our work investigates the mechanisms by which silencing is carried
out. We focus on two pathways: long
noncoding RNA- and sirtuin-mediated heterochromatin. Our group approaches the study of these
pathways by a combination of in vitro assembly of chromatin domains,
mechanistic biochemistry, proteomic analysis, and genome-wide chromatin
profiling to understand the complex superstructural “neighborhoods” of
Our group focuses on two main projects:
Uncovering mechanisms of long noncoding RNA(LncRNA)-mediated gene silencing. It has recently been appreciated that the
majority of the human genome has the capacity to be transcribed into RNA. Some of these non-protein coding RNA
products, made from what was once considered "junk DNA," can have
specific functions in the cell, such as contributing to gene regulation. We have focused on investigating the
molecular mechanism behind long noncoding RNAs that regulate
heterochromatin. Recently, we have
generated a new model for how a LncRNA called HOTAIR may choose its target
genes via RNA-RNA matchmaking. HOTAIR
has roles in developmental patterning and overexpression in cancer leads to
aberrant gene silencing that promotes aggressive cancer characteristics. By studying how LncRNAs work at the molecular
level, we have a shot at figuring out how to control them in disease to reset
normal epigenetic states.
Using budding yeast heterochromatin as a model to comprehensively characterize
a specific chromatin domain.
The genetics of budding yeast chromatin-mediated gene silencing have
provided an extensive foundation for understanding chromatin biology in all
eukaryotes. This model system is
distinguished by the minimal set of components necessary for gene silencing. The next step for this model is to provide
new insights through biochemistry. We
have demonstrated that a functional yeast heterochromatin domain can be
assembled in the test tube, and uncovered how versatile heterochromatic gene
silencing is, even in its most stripped-down form in budding yeast.
The interplay of heterochromatin and
Detailed biochemical analysis of
interactions between RNA Polymerase II and silencing factors.
Understanding the mechanism of directional
spreading of the silencing structure along a chromatin fiber.
How heterochromatin is re-established
in an epigenetic pattern.
Comprehensive characterization of the
yeast heterochromatin interactome using quantitative proteomics.