My long term research Interest is to investigate epigenetic mechanisms to suppress tumorigenesis. Recent
studies suggest that the DNA damage response (DDR) induced by aberrant proliferation, may be one of the
barriers at early stage of tumorigenesis to prevent genomic instability. One hallmark of DDR at early stage
of tumorigenesis Is histone H2A.X S139 phosphorylation (known as H2A.X). This phosphorylation event is
well-known for its demarcation of compact chromatin structures formed during DDR induced by DNA
damage agents. In keep with these observations, H2A.X deficiency accelerates the tumor progression on a
p53 deficient background in mice. Our preliminary studies have identified a new mark phosphorylation on
H2A.X, tyrosine 142 and its kinase, WSTF (William-Beuren Syndrome Transcription Factor), a gene
frequently deleted In human William-Beuren Syndrome (WS). Our studies have demonstrated that WSTF
has an intrinsic tyrosine kinase activity via its unconventional kinase domain, which shares no homology
with any known kinase fold. Interestingly, our recent data indicate that the WSTF and ATM may form a
"feed-forward" loop to regulate DDR induced by DNA damage treatment, including H2A.X (S139)
phosphorylation. WSTF may also play a critical role in DDR initiated by aberrant proliferation; therefore, it
may suppress tumorigenesis by preventing genomic instability. In the mentored phase, I will test if WSTF
function is regulated by the ATM/R kinases. A parallel objective in this phase is to develop H2A.X "designer
chromatin" in collaboration with Dr. Tom Muir's lab (Rockefeller University). In the independent phase, I will
test WSTF function for suppressing tumorigenesis in genetically modified mouse models. The goal of the
mentored phase (I year) is to develop key methodologies and reagents for the independent phase and
beyond. At the same time, I will apply for independent positions. The excellent environment in Drs. Allis
and Muir's lab will facilitate my research in the mentored phase and my transition to an independent
investigator. The proposed research at the independent phase (3 years) will pave the road to launch my
future investigations to Identify novel epigenetic mechanisms to suppress tumorigenesis. |