This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Gene silencing is a core cellular regulatory mechnaism. One form of silencing, conserved across eukaryotic kingdoms, involves histone H3 lysine 9 (H3K9) methylation, proteins of the HP1 family that recognize this modification, and, intriguingly, the RNAi machinery. Despite the conservation and significance of this mechanism, the fundamental questions of how this type of silencing is initiated, how RNAi promotes histone methylation, and how repression of gene expression is ultimately effected remain largely unanswered. To address these issues, we recently shifted our efforts from studies of the histone variant H2A.Z and other molecules that regulate silencing in S. cerevisiae (which lacks both H3K9 methylation and RNAi systems) to studies of silencing in the highly tractable fission yeast Schizosaccharomyces pombe. In this proposal, we seek to capitalize on a series of preliminary investigations in fission yeast already carried out in our laboratory to achieve a mechanistic understanding of gene silencing. This work will inform our understanding of repressive histone methylation, a mechanism that has been strongly implicated in the inactivation of tumor suppressor genes in human cancers.

Public Health Relevance

Our work focuses on understanding the mechanism of gene silencing mediated by repressive histone methylation. Since such mechanisms have been strongly implicated in the inactivation of tumor suppressor genes in human cancers, our fundamental insights into this conserved process will inform more applied studies of tumor biology. Our hope is that this will open up new avenues for the development of therapies that reactivate the expression of tumor suppressor genes and arrest growth and/or induce death of malignant cells.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
2P41RR011823-16
Application #
8365849
Study Section
Special Emphasis Panel (ZRG1-CB-L (40))
Project Start
2011-09-01
Project End
2012-06-30
Budget Start
2011-09-01
Budget End
2012-06-30
Support Year
16
Fiscal Year
2011
Total Cost
$12,768
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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