AMPK blocks starvation-inducible transgenerational defects in Caenorhabditis elegans

Abstract

Life history events, such as traumatic stress, illness, or starvation, can influence us through molecular changes that are recorded in a pattern of characteristic chromatin modifications. These modifications are often associated with adaptive adjustments in gene expression that can persist throughout the lifetime of the organism, or even span multiple generations. Although these adaptations may confer some selective advantage, if they are not appropriately regulated they can also be maladaptive in a context-dependent manner. We show here that during periods of acute starvation in Caenorhabditis elegans larvae, the master metabolic regulator AMP-activated protein kinase (AMPK) plays a critical role in blocking modifications to the chromatin landscape. This ensures that gene expression remains inactive in the germ-line precursors during adverse conditions. In its absence, critical chromatin modifications occur in the primordial germ cells (PGCs) of emergent starved L1 larvae that correlate with compromised reproductive fitness of the generation that experienced the stress, but also in the subsequent generations that never experienced the initial event. Our findings suggest that AMPK regulates the activity of the chromatin modifying COMPASS complex (complex proteins associated with Set1) to ensure that chromatin marks are not established until nutrient/energy contingencies are satisfied. Our study provides molecular insight that links metabolic adaptation to transgenerational epigenetic modification in response to acute periods of starvation.epigenetics | AMPK | histone methyltransferase | COMPASS | C. elegans

Surviving Starvation: AMPK Protects Germ Cell Integrity by Targeting Multiple Epigenetic Effectors

“…This period of quiescence is referred to as the L1 diapause . Our group and others noted that AMPK is required for the metabolic adjustment that occurs during this starved, developmentally quiescent diapause phase . We also showed that AMPK is required to block epigenetic modifications that ultimately affect the integrity of the germ line, which later has a negative impact on the reproductive capacity of these animals once they develop to the adult stage (Box and Table ).…”

“…In a recent study, we examined how the AMP activated protein kinase (AMPK), which has been well described for its role in maintaining energy homeostasis in response to several stresses, is also involved in blocking specific chromatin modifications and epigenetic changes in Caenorhabditis elegansCaenorhabditis elegans larvae that are subjected to starvation . In many animals, the disruption of both catalytic subunits, and hence all AMPK signaling, is lethal.…”

“…We also showed that AMPK is required to block epigenetic modifications that ultimately affect the integrity of the germ line, which later has a negative impact on the reproductive capacity of these animals once they develop to the adult stage (Box and Table ). The reproductive (Darwinian) fitness is further diminished in the AMPK mutant animals that were starved because the transgenerational defects affect the reproductive capacity of their progeny and that of the generations that follow …”

Stress Resets Transgenerational Small RNA Inheritance

“…Out of the 9 mutants defective in stress responses that we examined, only two (daf-16, aak-1/2) did not show altered RNAi inheritance dynamics. Interestingly, daf-16 was shown to be involved in heritable "mortal germline" phenotype (Mrt) (Simon et al, 2018) and aak-1/2 was implicated in regulating transgenerational consequences of starvation (Demoinet et al, 2017). The remaining 7 mutants showed either defective (mek-1/sek-1, kgb-1, hsf-1) or enhanced (pmk-1, sek-1, skn-1, daf-2)…”

Inter-generational Consequences for Growing C.elegans in Liquid

“…We found that the worms' concentration in liquid affects their size (p<0.0001, One-Way ANOVA), and that while in low concentrations the liquid-grown worms are longer ( Figure 1B and C), in very high concentrations, liquid-grown worms become shorter (perhaps in this condition not enough food is available). As starvation is known to generate heritable effects in C.elegans [8][9][10][11], in all the subsequent experiments we grew worms in liquid in low concentrations (maximum 0.05 worms per microliter, see methods).…”