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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Genetics A Study Section (MGA)
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Carter, Anthony D
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University of California San Francisco
Schools of Medicine
San Francisco
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Dumesic, Phillip A; Madhani, Hiten D (2014) Recognizing the enemy within: licensing RNA-guided genome defense. Trends Biochem Sci 39:25-34
Dumesic, Phillip A; Natarajan, Prashanthi; Chen, Changbin et al. (2013) Stalled spliceosomes are a signal for RNAi-mediated genome defense. Cell 152:957-68
Marina, Diana B; Shankar, Smita; Natarajan, Prashanthi et al. (2013) A conserved ncRNA-binding protein recruits silencing factors to heterochromatin through an RNAi-independent mechanism. Genes Dev 27:1851-6
Madhani, Hiten D (2013) The frustrated gene: origins of eukaryotic gene expression. Cell 155:744-9
Al-Sady, Bassem; Madhani, Hiten D; Narlikar, Geeta J (2013) Division of labor between the chromodomains of HP1 and Suv39 methylase enables coordination of heterochromatin spread. Mol Cell 51:80-91
Canzio, Daniele; Liao, Maofu; Naber, Nariman et al. (2013) A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly. Nature 496:377-81
Kiely, Christine M; Marguerat, Samuel; Garcia, Jennifer F et al. (2011) Spt6 is required for heterochromatic silencing in the fission yeast Schizosaccharomyces pombe. Mol Cell Biol 31:4193-204
Canzio, Daniele; Chang, Evelyn Y; Shankar, Smita et al. (2011) Chromodomain-mediated oligomerization of HP1 suggests a nucleosome-bridging mechanism for heterochromatin assembly. Mol Cell 41:67-81
Braun, Sigurd; Garcia, Jennifer F; Rowley, Margot et al. (2011) The Cul4-Ddb1(Cdt)ýý ubiquitin ligase inhibits invasion of a boundary-associated antisilencing factor into heterochromatin. Cell 144:41-54
Garcia, Jennifer F; Dumesic, Phillip A; Hartley, Paul D et al. (2010) Combinatorial, site-specific requirement for heterochromatic silencing factors in the elimination of nucleosome-free regions. Genes Dev 24:1758-71

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