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There is now a CONTENT FREEZE for Mercury while we switch to a new platform. It began on Friday, March 10 at 6pm and will end on Wednesday, March 15 at noon. No new content can be created during this time, but all material in the system as of the beginning of the freeze will be migrated to the new platform, including users and groups. Functionally the new site is identical to the old one. webteam@gatech.edu
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Title: The histone demethylase LSD1 represses stem cell genes during differentiation and in the prevention of neurodegeneration
Abstract:
We previously demonstrated in C. elegans that dimethylation of histone H3 on lysine 4 (H3K4me2) can serve as a stable epigenetic memory and that erasure of H3K4me2 by the histone demethylase LSD1/KDM1 in the germline prevents the inappropriate transmission of this epigenetic memory from one generation to the next. We now show in C. elegans that the SETDB1-like H3K9 methyltransferase, met-2, acts synergistically with lsd-1. These data suggest that H3K9me2 helps to prevent the transgenerational transmission of epigenetic memory by further repressing LSD1 targets. They also provide evidence that this novel germline reprogramming mechanism may function in the transgenerational inheritance of traits, such as longevity. To pursue the function of LSD1 further, we generated mice with germline mutations in Lsd1. Maternal loss of LSD1 results in embryonic arrest at the two-cell stage and these embryos fail to undergo the maternal to zygotic transition. This suggests that maternal reprogramming function of LSD1 is conserved. In addition we show that LSD1 is required in stem cell populations. Deletion of Lsd1 in the mouse testis results in sterility, with a complete failure to maintain the testis stem cell population, while loss of LSD1 in neural stem cells results in perinatal lethality shortly after birth. In both cases critical stem cell genes continue to be expressed alongside the expression of the differentiation program. These data suggest that LSD1 may be required to reprogram H3K4me2 to allow for the differentiation of stem cell populations. Remarkably, we also find that the inducible deletion of LSD1 in adult mice results in severe hippocampal neurodegeneration, and this neuronal loss is associated with the inappropriate reactivation of critical stem cell genes. This suggests that LSD1 may be part of endogenous epigenetic repressive mechanism that continually prevents differentiated cells from reverting to a stem cell fate. Taken together, our analysis of LSD1 in worms and mice provides evidence for epigenetic transcriptional memory and suggests that the regulation of this memory by LSD1 is fundamentally important for controlling the stem cell fate and key developmental transitions.
