Loss of the histone chaperone UNC-85/ASF1 inhibits the epigenome-mediated longevity and modulates the activity of one-carbon metabolism.

Histone H3/H4 chaperone anti-silencing function 1 (ASF1) is a conserved factor mediating nucleosomal assembly and disassembly, playing crucial roles in processes such as replication, transcription, and DNA repair. Nevertheless, its involvement in aging has remained unclear. Here, we utilized the model organism Caenorhabditis elegans to demonstrate that the loss of UNC-85, the homolog of ASF1, leads to a shortened lifespan in a multicellular organism. Furthermore, we show that UNC-85 is required for epigenome-mediated longevity, as knockdown of the histone H3 lysine K4 methyltransferase ash-2 does not extend the lifespan of unc-85 mutants. In this context, we found that the longevity-promoting ash-2 RNA interference enhances UNC-85 activity by increasing its nuclear localization. Finally, our data indicate that the loss of UNC-85 increases the activity of one-carbon metabolism, and that downregulation of the one-carbon metabolism component dao-3/MTHFD2 partially rescues the short lifespan of unc-85 mutants. Together, these findings reveal UNC-85/ASF1 as a modulator of the central metabolic pathway and a factor regulating a pro-longevity response, thus shedding light on a mechanism of how nucleosomal maintenance associates with aging.

Folate receptor overexpression induces toxicity in a diet-dependent manner in C. elegans.

Folate receptor (FR) alpha (FOLR1) and beta (FOLR2) are membrane-anchored folate transporters that are expressed at low levels in normal tissues, while their expression is strongly increased in several cancers. Intriguingly, although the function of these receptors in, for example, development and cancer has been studied intensively, their role in aging is still unknown. To address this, we utilized Caenorhabditis elegans, in which FOLR-1 is the sole ortholog of folate receptors. We found that the loss of FOLR-1 does not affect reproduction, physical condition, proteostasis or lifespan, indicating that it is not required for folate transport to maintain health. Interestingly, we found that FOLR-1 is detectably expressed only in uterine-vulval cells, and that the histone-binding protein LIN-53 inhibits its expression in other tissues. Furthermore, whereas knockdown of lin-53 is known to shorten lifespan, we found that the loss of FOLR-1 partially rescues this phenotype, suggesting that elevated folr-1 expression is detrimental for health. Indeed, our data demonstrate that overexpression of folr-1 is toxic, and that this phenotype is dependent on diet. Altogether, this work could serve as a basis for further studies to elucidate the organismal effects of abnormal FR expression in diseases such as cancer.

Bmi1+ Progenitor Cell Dynamics in Murine Cornea During Homeostasis and Wound Healing.

The outermost layer of the eye, the cornea, is renewed continuously throughout life. Stem cells of the corneal epithelium reside in the limbus at the corneal periphery and ensure homeostasis of the central epithelium. However, in young mice, homeostasis relies on cells located in the basal layer of the central corneal epithelium. Here, we first studied corneal growth during the transition from newborn to adult and assessed Keratin 19 (Krt19) expression as a hallmark of corneal maturation. Next, we set out to identify a novel marker of murine corneal epithelial progenitor cells before, during and after maturation, and we found that Bmi1 is expressed in the basal epithelium of the central cornea and limbus. Furthermore, we demonstrated that Bmi1+ cells participated in tissue replenishment in the central cornea. These Bmi1+ cells did not maintain homeostasis of the cornea for more than 3 months, reflecting their status as progenitor rather than stem cells. Finally, after injury, Bmi1+ cells fueled homeostatic maintenance, whereas wound closure occurred via epithelial reorganization. Stem Cells 2018;36:562-573.