Nobel Prize in Physiology or Medicine 2024

Although the soma ages during life, the germ line of multicellular organisms does not. Here it is shown that Caenorhabditis elegans mutants with increased longevity turn on gene expression programs in somatic tissue that are normally limited to the germ line; this may be the secret behind the increased health and lifespan of these mutant worms.

During fasting, cellular lipophagy is activated and lipid stores are catabolized. O’Rourke and Ruvkun identify two metabolic transcriptional regulators, MXL-3 and HLH-30, which orchestrate the adaptive response to fasting by modulating the expression of lysosomal lipases and autophagy genes. In addition, they show that these regulators can influence C. elegans aging.

Through RNAi screens in C. elegans, Ruvkun and colleagues identify signalling pathways that induce detoxification genes following disrupted translation, suggesting translational surveillance of toxins and virulence factors.

A genome-wide RNA interference screen in Caenorhabditis elegans identifies 45 genes with roles in protective pathways following drug- and genetic-disruption-induced mitochondrial inhibition.

To identify comprehensively factors involved in RNAi and microRNA-mediated gene expression regulation, this study performed a phylogenetic analysis of 86 eukaryotic species; the candidates this approach highlighted were subjected to Bayesian analysis with transcriptional and proteomic interaction data, identifying protein orthologues of already known RNAi silencing factors, as well as other hits involved in splicing, suggesting a connection between the two processes.

FOXO transcription factors confer stress resistance and longevity in several organisms. Ruvkun and colleagues demonstrate in Caenorhabditis elegans that DAF-16 (FOXO homologue) recruits the chromatin remodeller SWI/SNF to target genes. They show that SWI/SNF is required for DAF-16-mediated functions such as dauer formation, stress resistance and increasing longevity.

The transcription factor DAF-16/FOXO is a downstream effector of insulin/insulin-like growth factor signaling and plays an important role in stress resistance and longevity. Here, the authors show that DAF-16/FOXO can form a complex with HLH-30/TFEB to synergistically regulate transcription of target genes in response to certain stress stimuli.

Small RNAs — including miRNAs, siRNAs and piRNAs — differ in their biogenesis, modes of target regulation and biological functions. There are also interconnections between these pathways, which compete and collaborate in some of their regulatory and protective roles.

Our increasing understanding of microRNA biology, combined with sequence information from diverse animal genomes, has shed light on how microRNAs and their targets evolve and how the evolution of microRNA-containing regulatory networks has contributed to organismal complexity.

MicroRNAs are key regulators of gene expression. Emerging evidence points towards a reciprocal relationship between microRNAs and their targets and for roles of non-target RNAs and proteins in this crosstalk.

Germline mutations inDICER1 can lead to DICER1 syndrome, which is characterized by the predisposition of various types of cancer in childhood and during early adulthood. Additionally, specific DICER1 mutations occur in tumours. This Review discusses germline and somatically-acquired DICER1mutations and their effects on tumorigenesis.

The microRNA (miRNA) biogenesis pathway is frequently altered in cancer, leading to global downregulation of miRNA levels in some cancer types. This Review discusses the alterations that affect miRNA biogenesis in cancer.

MicroRNAs (miRNAs) repress gene expression both through initiating mRNA degradation and through translational repression. This Review describes how molecular studies and structural data are revealing key insights into both mechanisms of miRNA-mediated gene repression in animals, including their intricate interplay, and are posing new questions for future research.

miRNAs are crucial regulators of normal development in plants and animals, but their origins remain obscure. Exploration of the similarities and differences between different miRNA pathways help to elucidate their origins and role.

MicroRNAs (miRNAs) are key regulators of biological processes. Recent discoveries have expanded our understanding of the control of miRNA function in animals, through alternative processing, miRNA-sequence editing, post-translational modifications of Argonaute proteins, subcellular localization and regulation of miRNA–target interactions.

Pencheva and Tavazoie discuss the recent advances in understanding how microRNAs control metastatic progression in cancer.

A growing body of evidence implicates non-coding RNAs (ncRNAs) in liver carcinogenesis. In this Review, the authors summarize the pathological roles of ncRNAs in hepatocellular carcinoma and explore the potential applications of ncRNAs as diagnostic tools and therapeutic targets.

Developments in basic RNA biology have spawned RNA-based strategies to generate new types of therapeutics. Judy Lieberman reviews RNA-based drug design and discusses barriers to more widespread applications and possible ways to overcome them.

The cleavage of microRNA (miRNA) precursors by Drosha and Dicer and their loading with Argonaute proteins into RNA-induced silencing complexes are key steps in miRNA biogenesis. Recent studies have clarified the mechanisms of action of these molecular machines and discovered non-canonical miRNA biogenesis pathways.

Circulating microRNAs act as a new class of endocrine factor that can facilitate crosstalk between metabolic organs. This Review highlights obesity-associated and/or adipose tissue-enriched microRNAs and discusses their potential as biomarkers or therapeutics for obesity and related disorders.

In this Review, Brennan and Henshall discuss how microRNAs determine and control neuronal and glial functions, how this process is altered in states associated with hyperexcitability, and the prospects for microRNA targeting for the treatment of epilepsy.

MicroRNAs widely regulate systemic metabolism, prominently that of glucose and lipids. Consequently, microRNA misexpression can lead to metabolic diseases such as diabetes and atherosclerosis. MicroRNAs are therefore emerging as potential therapeutic targets to control metabolism and, owing to their secretion in extracellular vesicles, as metabolic biomarkers.

Shi et al. discuss recent approaches for the discovery of small noncoding RNAs (sncRNAs), limitations associated with sncRNA expression analyses, and emerging methods for direct and simultaneous detection of multiple RNA modifications.

In this Review, the authors describe how the application of new technologies to the microRNA (miRNA) field has yielded key insights into miRNA biology. The authors summarize our current understanding of miRNA biogenesis, function and processing, and highlight challenges to address in future research.

Circulating non-coding RNA (ncRNA) molecules are being investigated as biomarkers of endocrine tumours of the pituitary, parathyroid, pancreas and adrenal glands. This Review outlines ncRNA biology, before discussing research findings on ncRNAs in endocrine tumours and their potential utility as biomarkers, ending with an outlook for future studies.

In this Review, the authors describe our current knowledge of the role of microRNAs, long non-coding RNAs and circular RNAs in disease, with a focus on cardiovascular, neurological, infectious diseases and cancer. Further, they discuss the potential use of non-coding RNAs as disease biomarkers and as therapeutic targets.

Recent work suggests that microRNAs might have been important in the evolution of complexity in multicellular animals. Here it is shown that the most ancient known microRNA, miR–100, was initially active in neurosecretory cells around the mouth. Other highly conserved varieties were first present in specific tissues and organ systems. Thus, microRNA expression was initially restricted to an ancient set of ancient animal cell types and tissues.

This study reports a microscopy-based screen to find microRNAs (miRNAs) that control infection by Salmonella and Shigella, showing they have different requirements. Two miRNAs decrease Shigella actin motility through N-WASP and one miRNA inhibits Salmonella by targeting TGS2, a regulator of phagolysosomal trafficking.

Dror et al. report that melanoma-derived melanosomes carry miRNAs that induce primary fibroblast reprogramming into cancer-associated fibroblasts, and also induce the formation of a pro-tumorigenic niche.

Alexander van Oudenaarden and colleagues examine microRNA-mediated regulation of gene expression using single-cell measurements of a target gene's expression. They find that microRNAs can repress gene expression either as a switch or through fine-tuning and that the strength of repression can vary widely between cells.

C. elegans miRNAs associate with AGO proteins ALG-1 and ALG-2. Here the authors provide a map of miRNAs loaded into ALG-1 and ALG-2 from intestine, body wall muscles and nervous system in C. elegans providing insights into spatial and temporal AGO loading flexibility.

Germline small RNAs in plants and mammals are marked by pseudouridine. In plants, Exportin-t is required for pseudouridylation, transport and localization of small RNAs in pollen, as well as for epigenetic inheritance in the form the triploid block.

Wang et al. developed an inducible CRISPR–Cas9 system, in which guide RNA release is controlled by specific microRNAs, and demonstrated its application as a microRNA sensor and cell-type-specific genome regulator.

MicroRNAs are thought to confer robustness to biological processes, but clear experimental evidence is still needed. Here, Siciliano et al. construct a toggle-switch in mammalian cells to show that microRNAs buffer fluctuations in protein levels, thereby providing phenotypic robustness to gene regulatory networks.

The epithelial to mesenchymal transition (EMT) has been recently associated with a stem cell phenotype. In breast cancer cell lines and tumours, p53 directly targets the expression of microRNAs that have been shown to inhibit EMT and stem cells regulators.

Cellular senescence is partly caused by RB1/E2F-mediated repression of proliferation genes. Bischof and colleagues now demonstrate that RB1 interacts with the microRNA effector AGO2, and that AGO2 and the microRNA let-7 are needed for chromatin remodelling and repression of E2F-target loci.

RNA secondary structure is a new regulatory layer of transcript fates. Here, Li et al. find that plant RNA helicase Brr2a, acting beyond its canonical role in spliceosome, can optimize secondary structure of pri-miRNAs to promote miRNA production.

This study shows that the Arabidopsis TREX-2 complex coordinates the transcription, processing and export steps in miRNA biogenesis, and that it acts with the nucleoporin NUP1 in miRNA export.

Clinical insights from patients with a rare genetic skeletal disorder led to the discovery of the first case of a pathogenic gain-of-function miRNA mutation.

Miguel Moreno-Pelayo and colleagues report mutations in the seed region of human miR-96 segregating with progressive hearing loss in two families. In an accompanying paper, Karen Steel and colleagues show that the mouse diminuendo mutant, which also shows progressive hearing loss, carries a similar mutation in the seed region of mouse miR-96.

Human Long INterspersed Element class 1 (LINE-1) elements are expressed and mobilized in many types of cancer, contributing to malignancy. Here the authors show that the tumor suppressor microRNA let-7 targets the LINE-1 mRNA and reduces LINE-1 mobilization.

Victor Ambros and Gary Ruvkun identified a class of tiny molecules that have a crucial role in controlling gene expression.

In some organisms a reduced-calorie diet increases lifespan. Conventional thinking about the mechanism involved now comes under question from the results of experiments with yeast.

Two studies in nematodes revolutionized our understanding of gene regulation by identifying and functionally characterizing the first microRNA, lin-4.

Ule and colleagues discuss cross-linking and immunoprecipitation (CLIP) methods for characterizing the RNA binding partners of RNA-binding proteins and explore the data analysis workflows, best practices and applications for these techniques. The Primer also considers methods for characterizing the protein binding partners of specific RNAs and discusses how data from these complementary methods can be integrated into CLIP workflows.

Two recent studies provide mechanistic insights into how LIN28A controls changes in cell fate identity, focusing on either a let-7-independent or let-7-dependent pathway of action involving LIN28A.

Analysis of publication data sheds light on the people, institutions and concepts at the heart of research. Powered by Nature Navigator.