THE ROLES OF SET-9 AND SET-26 IN LONGEVITY, GERMLINE FUNCTION AND RNAI PATHWAY May 2018
Aging, germline function and RNA interference are three distinct biological processes that associate with alterations in epigenetic state, including histone modifications. Our lab discovered two highly homologous SET domain containing genes, set-9 and set-26, in an RNAi screen of putative histone methyltransferases that regulate lifespan in C. elegans. Inactivating set-9/set-26 consistently extends lifespan. However, both the molecular functions of SET-9 and SET-26 and whether they are also involved in other biological processes are largely unknown. My work found that SET-26 but not SET-9 plays an important role in lifespan regulation. Endogenous SET-26 is broadly expressed while SET-9 is only detectable in the germline. Specifically, somatically expressed SET-26 is implicated in lifespan determination. Transcriptional profile revealed that the somatic SET-26 regulated DAF-16-dependent genes are enriched for lifespan determinant genes, which likely explain the long-lived lifespan phenotype of set-26 mutant. Moreover, SET-9 and SET-26 act redundantly to regulate germline function. Molecular analyses showed that SET-9 and SET-26 bind to H3K4me3 both in vitro and in vivo. Germline-expressed SET-9 and SET-26 normally bind to and restrict H3K4me3. Loss of SET-9 and SET-26 causes spreading of this mark with a bias towards 3’ end. The spreading of H3K4me3 correlates with elevated expression of a group of germline specific genes, which could explain the fertility defect in the set-9 set-26 double mutant. In addition to longevity and germline function, I found that SET-26 is also involved in RNAi-mediated gene silencing. SET-26 is required for dsRNA-induced H3K9me3 but not H3K27me3 deposition. SET-9 and SET-26 are putative homologs of the human protein Mixed Lineage Leukemia 5 (hMLL5), which plays an important role in regulating hematopoietic homeostasis, cell cycle and survival. However, the molecular basis underlying hMLL5 activity is still unknown. Our findings on SET-9 and SET-26 will help us better understand the role of hMLL5 in human and also implicated hMLL5 in germline function and longevity. 2018
Lee, Siu Sylvia
Soloway, Paul; Danko, Charles G.
Biochemistry, Molecular and Cell Biology
Ph. D., Biochemistry, Molecular and Cell Biology
Doctor of Philosophy
dissertation or thesis