Uncovering the genes, variants, and interactions underlying crop diversity is a frontier in plant genetics. Phenotypic variation often does not reflect the cumulative effect of individual gene mutations. This deviation is due to epistasis, in which interactions between alleles are often unpredictable and quantitative in effect. Recent advances in genomics and genome-editing technologies are elevating the study of epistasis in crops. Using the traits and developmental pathways that were major targets in domestication and breeding, we highlight how epistasis is central in guiding the behavior of the genetic variation that shapes quantitative trait variation. We outline new strategies that illuminate how quantitative epistasis from modified gene dosage defines background dependencies. Advancing our understanding of epistasis in crops can reveal new principles and approaches to engineering targeted improvements in agriculture. Expected final online publication date for the Annual Review of Genetics, Volume 54 is November 23, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

• PMID: 32870731
• DOI: 10.1146/annurev-genet-050720-122916

The ventromedial nucleus of the hypothalamus (VMN) is involved in the counterregulatory response to hypoglycemia. VMN neurons activated by hypoglycemia (glucose inhibited, GI neurons) have been assumed to play a critical, although untested role in this response. Here, we show that expression of a dominant negative form of AMP-activated protein kinase (AMPK) or inactivation of AMPK α1 and α2 subunit genes in Sf1 neurons of the VMN selectively suppressed GI neuron activity. We found that Txn2, encoding a mitochondrial redox enzyme, was strongly down-regulated in the absence of AMPK activity and that reexpression of Txn2 in Sf1 neurons restored GI neuron activity. In cell lines, Txn2 was required to limit glucopenia-induced ROS production. In physiological studies, absence of GI neuron activity following AMPK suppression in the VMN had no impact on the counterregulatory hormone response to hypoglycemia nor on feeding. Thus, AMPK is required for GI neuron activity by controlling the expression of the anti-oxidant enzyme Txn2. However, the glucose sensing capacity of VMN GI neurons is not required for the normal counterregulatory response to hypoglycemia. Instead, it may represent a fail-safe system in case of impaired hypoglycemia sensing by peripherally located gluco-detection systems that are connected to the VMN.

• PMID: 32839348
• DOI: 10.2337/db20-0577

Nonsense-mediated mRNA decay (NMD) is a translation-dependent RNA degradation pathway that is important for the elimination of faulty, and the regulation of normal, mRNAs. The molecular details of the early steps in NMD are not fully understood but previous work suggests that NMD activation occurs as a consequence of ribosome stalling at the termination codon (TC). To test this hypothesis, we established an in vitro translation-coupled toeprinting assay based on lysates from human cells that allows monitoring of ribosome occupancy at the TC of reporter mRNAs. In contrast to the prevailing NMD model, our in vitro system reveals similar ribosomal occupancy at the stop codons of NMD-sensitive and NMD-insensitive reporter mRNAs. Moreover, ribosome profiling reveals a similar density of ribosomes at the TC of endogenous NMD-sensitive and NMD-insensitive mRNAs in vivo. Together, these data show that NMD activation is not accompanied by stable stalling of ribosomes at TCs.

• PMID: 32807779
• PMCID: PMC7431590
• DOI: 10.1038/s41467-020-17974-z

Hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH), the “master molecule” regulating reproduction and fertility, migrate from their birthplace in the nose to their destination using a system of guidance cues, which include the semaphorins and their receptors, the neuropilins and plexins, among others. Here, we show that selectively deleting neuropilin-1 in new GnRH neurons enhances their survival and migration, resulting in excess neurons in the hypothalamus and in their unusual accumulation in the accessory olfactory bulb, as well as an acceleration of mature patterns of activity. In female mice, these alterations result in early prepubertal weight gain, premature attraction to male odors, and precocious puberty. Our findings suggest that rather than being influenced by peripheral energy state, GnRH neurons themselves, through neuropilin-semaphorin signaling, might engineer the timing of puberty by regulating peripheral adiposity and behavioral switches, thus acting as a bridge between the reproductive and metabolic axes.

The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression¹. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.