Previous studies of MES-4 have shown that it is an autosomally enriched histone methyltransferase that participates in X chromosome silencing in C. elegans. The work proposed here will determine how MES-4 can act from afar to control X chromosome expression and find proteins that work with MES-4 in this process. Additionally, this work will further our understanding of the function of SET domain proteins, many of which have been shown to be mutated in cancer, including the human homolog of MES-4, NSD-1.
The specific aims of this proposal are (1) to use germline overexpression of MES-4 to test whether it acts as an """"""""anti-promiscuity factor;"""""""" (2) to test suppressors of SynMuv B mutants for their roles in the mes-4 pathway, and (3) to use epitope-tagged MES-4 to perform biochemical pull-downs of MES-4 interacting proteins. Using overexpression analysis, it will be tested whether MES-4 acts similarly to yeast Dot1 as an """"""""antipromiscuity- factor"""""""" and in this manner can control the chromatin state of the X chromosome while residing on the autosomes. In order to find other proteins that act with MES-4, use of a two-pronged genetic and biochemical approach will be used. Candidate genes that have similar phenotypes to mes-4 in the soma will be tested in the germ line for their potential roles in the MES-4 pathway. Additionally, a modified tandem affinity tag pull-down system will be used to purify and identify MES-4 interactors. Relevance: Misregulation of gene expression underlies many diseases and cancer. Mutations in a group of proteins called histone methyltransferases, which control gene expression via regulation of chromatin, have been shown to lead to cancer, including the human version of the C. elegans protein MES-4. This research will investigate the role of MES-4 in the control gene expression in the C. elegans germ line and will look for other proteins that act with MES-4 in this process.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM083548-03
Application #
7762846
Study Section
Special Emphasis Panel (ZRG1-F05-J (20))
Program Officer
Carter, Anthony D
Project Start
2008-02-01
Project End
2011-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
3
Fiscal Year
2010
Total Cost
$52,154
Indirect Cost
Name
University of California Santa Cruz
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Petrella, Lisa N; Wang, Wenchao; Spike, Caroline A et al. (2011) synMuv B proteins antagonize germline fate in the intestine and ensure C. elegans survival. Development 138:1069-79
Spencer, W Clay; Zeller, Georg; Watson, Joseph D et al. (2011) A spatial and temporal map of C. elegans gene expression. Genome Res 21:325-41