Authors:

Zara Keshwani

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About Paper:

Epigenetic marks, such as post-translational modifications to histones, are regulators of aging and longevity. A decrease in trimethylated histone levels H3 on lysine 4, known as H3K4me3, is known to extend lifespan and increase stress resistance in C. elegans. Preliminary work from the Jakob lab has started to identify signaling pathways that link changes in H3K4me3 levels to lifespan, including the transcription factor helix-loop-helix 30 (HLH-30) and its mammalian ortholog transcription factor EB (TFEB). Knockdown of a protein involved in the deposition of H3K4me3, ASH-2, leads to lower levels of H3K4me3 and increased lifespan. We have observed that this increase in lifespan requires the presence of HLH-30/TFEB, as C. elegans mutants lacking HLH-30 no longer benefit from ASH-2 knockdown. We are interested in investigating the mechanisms underlying this H3K4me3-HLH-30 longevity axis, specifically how HLH-30/TFEB is regulated in C. elegans and mammalian cells when ASH-2 is knocked down and H3K4me3 levels are lowered. Preliminary data have indicated that mRNA/protein levels of TFEB are not altered by ASH-2 knockdown in HEK293 cells. TFEB activity is also regulated by subcellular localization, with TFEB being retained and inactive in the cytosol under normal conditions and translocating to the nucleus during stress conditions. We find that when HEK293 cells are subject to heat stress, more TFEB translocates to the nucleus in cells lacking ASH-2. These findings suggest that TFEB may be primed to be activated under stress conditions when ASH-2 is not present and H3K4me3 levels are lowered. We are further interested in studying whether ASH-2 knockdown increases TFEB presence in the nucleus compared to the cytoplasm under other TFEB-activating conditions, as with Torin-1. Our experiments are focused on the effects of heat stress and Torin-1 on TFEB levels, nuclear localization, and transcription of TFEB-dependent genes under normal and ASH-2 knockdown conditions. COOH OSS OOOO SSO SCH OC PSO OSLO OCHO GC OHO OHO OL OOOCOOOHOOO ©FFDFDDDIDFDFIDDIDDIDIFHIDDIDDDDIDDIDDDDIFVIHDIIDIODDD

Source:

Chicago Area Undergraduate Research Symposium

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Co-authors:

Zara Keshwani