Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress

Abstract

To better understand the mechanisms that regulate stem cell identity and function we sought to identify genes that are preferentially expressed by stem cells and critical for their function in multiple tissues. Prdm16 is a transcription factor that regulates leukemogenesis1, palatogenesis2, and brown fat development3–5, but which was not known to be required for stem cell function. We demonstrate that Prdm16 is preferentially expressed by stem cells throughout the nervous and hematopoietic systems and required for their maintenance. Prdm16 deficiency led to changes in reactive oxygen species (ROS) levels, increased cell death, altered cell cycle distribution, and stem cell depletion in the hematopoietic and nervous systems. In neural stem/progenitor cells, Prdm16 bound the Hgf promoter and in the absence of Prdm16 Hgf expression declined. Addition of recombinant HGF to culture partially rescued the increase in ROS levels and the depletion of Prdm16 deficient neural stem cells. Administration of the anti-oxidant, N-acetyl-cysteine, to Prdm16 deficient mice partially rescued defects in neural stem/progenitor cell function and neural development. Prdm16 therefore promotes stem cell maintenance in multiple tissues, partly by modulating oxidative stress.

Day–night cycles and the sleep-promoting factor, Sleepless, affect stem cell activity in the Drosophila testis

“…Alternatively, oxidative stress could contribute to the altered stem cell activity in sss mutants. Sleep-deprived flies exhibit elevated levels of reactive oxygen species in the brain and possibly other tissues (3), and oxidative stress was shown to affect stem cell niches by stimulating stem cell division (48,49) and inducing differentiation (50). Although reactive oxygen species or altered immune function have not been linked to the sleep phenotype of sss mutants, GABA signaling is shown to mediate reduced sleep levels in these flies, and our study has implicated its involvement in increased stem cell divisions, supporting a mechanistic link between sleep and the regulation of stem cells.…”

Epigenetic regulation of aging stem cells

“…Tissue-specific transcription factors control adult stem cell maintenance through regulation of stem cell differentiation, self-renewal and response to environmental stimuli and damage Dumble et al, 2007;Su et al, 2009;Chuikov et al, 2010). Altered activity of transcription factors in adult stem cell compartments is linked to premature aging phenotypes Dumble et al, 2007;Su et al, 2009).…”

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

“…Animal experiments have shown relations to superoxide and oxidative stress 79 . Six genes with known links to oxidative stress and NO, within these 38 loci were identified (REST 48 , GJA1 49 , YAP1 50 , PRDM16 51 , LRP1 52 , and MRVI1 53 ). This is in line with previous findings 16 , however, in the DEPICT pathway analysis we found that NO-related reconstituted gene sets were not significantly associated with migraine (FDR > 0.54) (Supplementary Table 15).…”

“…Six of the loci harbor genes that are involved in nitric oxide signaling and oxidative stress (REST 48 , GJA1 49 , YAP1 50 , PRDM16 51 , LRP1 52 , and MRVI1 53 ).…”