Dietary restriction (DR), a reduction in nutrient intake without malnutrition, is the most reproducible way to extend lifespan in a wide range of organisms across the tree of life, yet the evolutionary underpinnings of the DR effect on lifespan are still widely debated. The leading theory suggests that this effect is adaptive and results from reallocation of resources from reproduction to somatic maintenance, in order to survive periods of famine in nature. However, such response would cease to be adaptive when DR is chronic and animals are selected to allocate more resources to reproduction. Nevertheless, chronic DR can also increase the strength of selection resulting in the evolution of more robust genotypes. We evolved Drosophila melanogaster fruit flies on 'DR', 'standard' and 'high' adult diets in replicate populations with overlapping generations. After approximately 25 generations of experimental evolution, male 'DR' flies had higher fitness than males from 'standard' and 'high' populations. Strikingly, this increase in reproductive success did not come at a cost to survival. Our results suggest that sustained DR selects for more robust male genotypes that are overall better in converting resources into energy, which they allocate mostly to reproduction.

One of the key tenets of life-history theory is that reproduction and survival are linked and that they trade-off with each other. When dietary resources are limited, reduced reproduction with a concomitant increase in survival is commonly observed. It is often hypothesized that this dietary restriction effect results from strategically reduced investment in reproduction in favor of somatic maintenance to survive starvation periods until resources become plentiful again. We used experimental evolution to test this "waiting-for-the-good-times" hypothesis, which predicts that selection under sustained dietary restriction will favor increased investment in reproduction at the cost of survival because "good-times" never come. We assayed fecundity and survival of female Drosophila melanogaster fruit flies that had evolved for 50 generations on three different diets varying in protein content-low (classic dietary restriction diet), standard, and high-in a full-factorial design. High-diet females evolved overall increased fecundity but showed reduced survival on low and standard diets. Low-diet females evolved reduced survival on low diet without corresponding increase in reproduction. In general, there was little correspondence between the evolution of survival and fecundity across all dietary regimes. Our results contradict the hypothesis that resource reallocation between fecundity and somatic maintenance underpins life span extension under dietary restriction.

ENCODE 3 (2012-2017) expanded production and added new types of assays 8 (Fig. 1, Extended Data Fig. 1), which revealed landscapes of RNA binding and the 3D organization of chromatin via methods such as chromatin interaction analysis by paired-end tagging (ChIA-PET) and Hi-C chromosome conformation capture. Phases 2 and 3 delivered 9,239 experiments (7,495 in human and 1,744 in mouse) in more than 500 cell types and tissues, including mapping of transcribed regions and transcript isoforms, regions of transcripts recognized by RNA-binding proteins, transcription factor binding regions, and regions that harbour specific histone modifications, open chromatin, and 3D chromatin interactions. The results of all of these experiments are available at the ENCODE portal (http://www.encodeproject.org). These efforts, combined with those of related projects and many other laboratories, have produced a greatly enhanced view of the human genome (Fig. 2), identifying 20,225 protein-coding and 37,595 noncoding genes

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Human naive pluripotent stem cells have unrestricted lineage potential. Underpinning this property, naive cells are thought to lack chromatin-based lineage barriers. However, this assumption has not been tested. Here we define the chromatin-associated proteome, histone post-translational modifications and transcriptome of human naive and primed pluripotent stem cells. Our integrated analysis reveals differences in the relative abundance and activities of distinct chromatin modules. We identify a strong enrichment of polycomb repressive complex 2 (PRC2)-associated H3K27me3 in the chromatin of naive pluripotent stem cells and H3K27me3 enrichment at promoters of lineage-determining genes, including trophoblast regulators. PRC2 activity acts as a chromatin barrier restricting the differentiation of naive cells towards the trophoblast lineage, whereas inhibition of PRC2 promotes trophoblast-fate induction and cavity formation in human blastoids. Together, our results establish that human naive pluripotent stem cells are not epigenetically unrestricted, but instead possess chromatin mechanisms that oppose the induction of alternative cell fates.