Annual review of genetics最新文献

Epigenetic mechanisms are essential for gene expression regulation. Recent advances have revealed how cells not only stabilize transcriptional states but also actively prepare for future gene expression. This review explores four processes in epigenetic preparation for future gene induction: priming, reining, transcriptional memory, and transcriptional tolerance. Priming establishes chromatin configurations that facilitate future gene activation without immediate transcription. Conversely, reining balances responsiveness with transcriptional stability to prevent premature gene activation or overexpression. Transcriptional memory facilitates faster and stronger responses to recurrent stimuli by reflecting past activation events, whereas transcriptional tolerance imposes restraint on subsequent activation. We examine how these mechanisms, involving DNA methylation, histone modification, and chromatin remodeling, integrate with signaling pathways and transcription factors to orchestrate future gene induction. Leveraging recent insights from mammalian systems, this review highlights the emerging role of epigenetic preparation in adaptive cellular responses, with implications for development, disease, and cellular memory in mammals.

The MAP3K dual-leucine zipper kinases are stress-sensing signaling molecules that have important roles in neuronal development and maintenance, traumatic injury, and neurodegeneration. These kinases activate signal transduction cascades and elicit distinct cellular phenotypes in response to a variety of physiological and pathological stimuli. Studies from animal and cellular models have supported their conserved functions and also highlight context and cell-type specificity. This review focuses on recent findings on the molecular landscape associated with these kinases and discusses key themes of the DLK function network in the mammalian nervous system.

Decades of research into the noncoding transcriptome have unveiled a complex, multilayered web of molecular interactions that govern gene expression, protein synthesis, and cellular function, challenging the once-presumed linear simplicity of the flow of genetic information. In bacteria, highly diverse small RNAs (sRNAs) play a crucial role in gene expression, often acting at the heart of large regulatory networks to modulate cellular processes through direct base-pairing interactions with target messenger RNAs (mRNAs). The expression of most sRNAs is tightly controlled at the level of transcription, but RNA sponges have recently emerged as an additional layer of regulation restricting sRNA activity and abundance. By titrating sRNAs and influencing their interactions with target mRNAs and RNA-binding proteins, RNA sponges contribute to the fine-tuning of global gene expression networks. In addition, the integration of RNA sponges into functional loops promotes elegant crosstalk between major regulons at the posttranscriptional level.

Hibernation is a fascinating adaptation to food-scarce winters, characterized by significant physiological and behavioral changes, including fasting, inactivity, and insulin resistance. While hibernation is critical for the survival of many species, hibernation-related traits are often considered pathological in humans. Hibernation has been studied from a genomic perspective, especially with respect to transcription across multiple tissues. These studies have identified the differential activity of signaling pathways related to metabolism, tissue protection, and other mechanisms likely underlying hibernation phenotypes. Bears, in particular, are an interesting model for physiological and genomic studies of hibernation due to their large size and unique mode of hibernation compared to other small mammalian hibernators. Investigating the intricate molecular mechanisms underlying bear hibernation may therefore provide insight into fundamental biological processes with potential translational implications for human health, particularly with respect to metabolic disorders such as type II diabetes. This review focuses on recent advances and outstanding questions related to the exploration of bear hibernation from a genomic perspective.

The natural world is full of valuable lessons about genetic adaptation as organisms respond to changing conditions around them. Deciphering these changes is a major goal of evolutionary genetics. Advances have been made through phylogenomic approaches using the wealth of closely related genome sequences in mammals. These studies bring us lessons about the adaptive capacity allowed by the evolutionary process as well as the underlying genetic mechanisms controlling important traits. Diverse methods are now routinely used to identify the genetic basis of these adaptations. These reveal new functions of genes and regulatory regions that have responded to changes in lifestyle, such as aquatic life and flight, as well as major life history axes, such as lifespan. Phylogenomic studies have been equally revealing of specific traits that evolve in response to different selective pressures, such as hair formation and vocal learning. These approaches continue to develop to overcome challenges inherent in information-poor regulatory regions to find changes to gene regulatory networks as well. The development of these approaches is expected to accelerate as new tools, such as machine learning models, are incorporated and deployed on ever denser phylogenies containing new interesting traits.

The adult human brain, under resting conditions, consumes approximately 20% of total body glucose, a demand that is even higher during the first decade of life. The brain metabolic landscape is intricately regulated throughout development, and each cell type exhibits distinct metabolic signatures at each specific stage. This picture becomes even more intricate when considering that metabolism is dynamically modulated to sustain critical biological processes, such as cell proliferation and differentiation and synaptic activity-dependent processes. The orchestration between metabolic regulation and the aforementioned physiological processes often relies on metabolism-dependent changes in the epigenetic landscape, which shape gene expression patterns to trigger selected downstream biological responses. Perturbations of brain metabolic pathways are frequently the cause of severe neurodevelopmental disorders. This review explores the latest insights into the regulation of brain metabolism in health and disease.

Cochlear hair cells are epithelial cells that are not replaced when lost, leading to permanent hearing loss. The lack of spontaneous regeneration of hair cells is a rarity in epithelial tissues, including hair cell epithelia. Evolutionary considerations may explain why hair cell regenerative capacity of mammals was lost during the evolution of the cochlea. In parallel, at the molecular level, studies using transgenesis and developmental biology have revealed some of the key signaling molecular players that govern the development of hair cells and their neighboring supporting cells and provided candidates for manipulating the system to induce regeneration. Gene transfer technology using viruses showed proof of principle for the ability to induce the transdifferentiation of supporting cells to new hair cells, but the outcome is inconsistent and of low quantity and poor quality. Further use of modern sequencing technology should reveal additional details of gene expression and its regulation in the process of regenerating hair cell organs such as in fish, birds, and mammalian balance organs. Sequence data generated from supporting cells in mature ears with hair cell lesions, at the level of gene expression and its epigenetic regulation, will assist in designing these therapeutic interventions. Still, rebuilding a perfect new cochlea to provide normal hearing in profoundly deaf ears remains a formidable challenge.

Trained as a biochemist and molecular biologist, in 1975, I began to work on Drosophila maternal mutants with the aim to isolate morphogens. As group leaders at the European Molecular Biology Laboratory in Heidelberg, Germany, Eric Wieschaus and I discovered 120 genes that control embryonic development. Many of them turned out to be members of important developmental pathways conserved throughout the animal phyla. This work was honored with the Nobel Prize in 1995. Genetic analysis of the maternal contribution to embryogenesis led to the first identification of a morphogenetic gradient. The transcription factor Bicoid determines position along the Drosophila anteroposterior axis in a concentration-dependent manner. To identify genes specific to vertebrate development, my lab undertook a large-scale screen for mutants in the small zebrafish Danio rerio, establishing it as a powerful vertebrate model system. The last projects in my lab concerned the formation and evolution of the color pattern of zebrafish and related species.

The Red Queen model of antagonistic coevolution has been the preferred explanation for certain biological phenomena, such as extreme genetic diversity and trans-species polymorphisms in disease genes. This model has been studied on diverse timescales using direct observations (covering days to a few years), archived material (several decades), postglacial processes (about 10,000 years), and phylogeographic and phylogenetic methods (millions of years). Here, I review the evidence for specific antagonistic coevolution in the host-parasite Daphnia-Pasteuria model system, paying particular attention to the timescales addressed by different approaches. Microevolutionary studies of the coevolutionary process are congruent with macroevolutionary patterns observed in phylogeographic contexts and deep time. This evidence strongly supports the Red Queen model, providing a powerful explanation for the extraordinary genetic diversity seen in host and parasite disease genes.

The formation and maintenance of the finite mammalian ovarian reserve are critical for fertility and species survival. Genetic and developmental studies have uncovered various mechanisms underlying oocyte development and maturation, revealing two curious features of the ovarian germline: (a) The establishment of the follicle reserve involves an initial massive overproduction of oocyte precursors, and (b) the total number of ovulated oocytes across an animal's fertile lifetime is a very small proportion of the initial ovarian reserve. Many have proposed that this indicates the existence of selective quality control to ensure gamete fitness. Here, we review the findings underlying the hypotheses for germline quality control during prepubertal development, homeostatic fertility, and reproductive aging. We evaluate whether the existing evidence base distinguishes the active selection of specific germ cell subsets from neutral dynamics. Throughout, we discuss strategies for applying statistical frameworks to evaluate selection in oogenesis and the implications of neutrality versus selection at various points in oocyte development.