Current Opinion in Genetics & Development最新文献

Temperature exerts a fundamental influence across scales of biology, from the biophysical nature of molecules, to the sensitivity of cells, and the coordinated progression of development in embryos. Species-specific developmental rates and temperature-induced acceleration of development indicate that these sensing mechanisms are harnessed to influence developmental dynamics. Tracing how temperature sensitivity propagates through biological scales to influence the pace of development can therefore reveal how embryogenesis remains robust to environmental influences. Cellular protein homeostasis (proteostasis), and cellular metabolic rate are linked to both temperature-induced and species-specific developmental tempos in specific cell types, hinting toward generalized mechanisms of timing control. New methods to extract timing information from single-cell profiling experiments are driving further progress in understanding how mechanisms of temperature sensitivity can direct cell-autonomous responses, coordination across cell types, and evolutionary modifications of developmental timing.

The activation of genes within the nucleus of eukaryotic cells is a tightly regulated process, orchestrated by a complex interplay of various physical properties and interacting factors. Studying the multitude of components and features that collectively contribute to gene activation has proven challenging due to the complexities of simultaneously visualizing the dynamic and transiently interacting elements that coalesce within the small space occupied by each individual gene. However, various labeling and imaging advances are now starting to overcome this challenge, enabling visualization of gene activation at different lengths and timescales. In this review, we aim to highlight these microscopy-based advances and suggest how they can be combined to provide a comprehensive view of the mechanisms regulating gene activation.

Methylation of histone H3 on the lysine-4 residue (H3K4me) is found throughout the eukaryotic domain, and its initial discovery as a conserved epigenetic mark of active transcription from yeast to mammalian cells has contributed to the histone code hypothesis. However, recent studies have raised questions on whether the different forms of H3K4me play a direct role in gene regulation or are simply by-products of the transcription process. Here, we review the often-conflicting experimental evidence, focusing on the monomethylation of lysine 4 on histone H3 that has been linked to the transcriptional state of enhancers in metazoans. We suggest that this epigenetic mark acts in a context-dependent manner to directly facilitate the transcriptional output of the genome and the establishment of cellular identity.

Specifically timed pulses of the moulting hormone ecdysone are necessary for developmental progression in insects, guiding development through important milestones such as larval moults, pupation and metamorphosis. It also coordinates the acquisition of cell identities, known as cell patterning, and growth in a tissue-specific manner. In the absence of ecdysone, the ecdysone receptor heterodimer Ecdysone Receptor and Ultraspiracle represses expression of target primary response genes, which become de-repressed as the ecdysone titre rises. However, ecdysone signalling elicits both repressive and activating responses in a temporal and tissue-specific manner. To understand how ecdysone achieves such specificity, this review explores the layers of gene regulation involved in stage-appropriate ecdysone responses in Drosophila fruit flies.

The circadian clocks are cell-autonomous intrinsic oscillators existing throughout the body to coordinate intracellular and intercellular functions of each organ or tissue. The circadian clock oscillation gradually emerges during mid-to-late gestation in the mammalian developmental process. Recently, it has been revealed that the in vitro differentiation of mouse ES cells recapitulates the circadian clock development. Moreover, reprogramming of the cells results in the redisappearance of the clock, indicating that circadian clocks are tightly coupled with cellular differentiation. Interestingly, before the circadian clock develops, the embryo is governed under ultradian rhythms driven by the segmentation clock. This short review explores these observations, discussing the significance of the emergence of circadian clock oscillation during the mammalian developmental process.

High-resolution Micro-C maps identified a specialized class of regulatory DNAs termed ‘tethering elements’ (TEs) in Drosophila. These 300–500-bp elements facilitate specific long-range genomic associations or loops. The POZ-containing transcription factor GAF (GAGA-associated factor) contributes to loop formation. Tether–tether interactions accelerate Hox gene activation by distal enhancers, and coordinate transcription of duplicated genes (paralogs) through promoter–promoter associations. Some TEs engage in ultra-long-range enhancer–promoter and promoter–promoter interactions (meta-loops) in the Drosophila brain. We discuss the basis for tether–tether specificity and speculate on the occurrence of similar elements in vertebrate genomes.

Nuclear organization has emerged as a critical layer in the coordination of DNA repair activities. Distinct types of DNA lesions have notably been shown to relocate at the vicinity of nuclear pore complexes (NPCs), where specific repair pathways are favored, ultimately safeguarding genome integrity. Here, we review the most recent progress in this field, notably highlighting the increasingly diverse types of DNA structures undergoing repositioning, and the signaling pathways involved. We further discuss our growing knowledge of the molecular mechanisms underlying the choice of repair pathways at NPCs, and their conservation — or divergences. Intriguingly, a series of recent findings suggest that DNA metabolism may be coupled to NPC biogenesis and specialization, challenging our initial vision of these processes.

The rate of development is highly variable across animal species. However, the mechanisms regulating developmental tempo have remained elusive due to difficulties in performing direct interspecies comparisons. Here, we discuss how pluripotent stem cell-based models of development can be used to investigate cell- and tissue-autonomous temporal processes. These systems enable quantitative comparisons of different animal species under similar experimental conditions. Moreover, the constantly growing stem cell zoo collection allows the extension of developmental studies to a great number of unconventional species. We argue that the stem cell zoo constitutes a powerful platform to perform comparative studies of developmental tempo, as well as to study other forms of biological time control such as species-specific lifespan, heart rate, and circadian clocks.

DNA methylation is a conserved epigenetic modification associated with transposon silencing and gene regulation. The stability of this modification relies on intimate connections between DNA and histone modifications that generate self-reinforcing loops wherein the presence of one mark promotes the other. However, it is becoming increasingly clear that the efficiency of these loops is affected by cross-talk between pathways and by chromatin accessibility, which is heavily influenced by histone variants. Focusing primarily on plants, this review provides an update on the aforementioned self-reinforcing loops, highlights recent advances in understanding how DNA methylation pathways are restricted to prevent encroachment on genes, and discusses the roles of histone variants in compartmentalizing epigenetic pathways within the genome. This multilayered approach facilitates two essential, yet opposing functions, the ability to maintain heritable DNA methylation patterns while retaining the flexibility to modify these patterns during development.

Microglia are the major immune cells of the central nervous system (CNS) that perform numerous adaptive functions required for normal CNS development and homeostasis but are also linked to neurodegenerative and behavioral diseases. Microglia development and function are strongly influenced by brain environmental signals that are integrated at the level of transcriptional enhancers to drive specific programs of gene expression. Here, we describe a conceptual framework for how lineage-determining and signal-dependent transcription factors interact to select and regulate the ensembles of enhancers that determine microglia development and function. We then highlight recent findings that advance these concepts and conclude with a consideration of open questions that represent some of the major hurdles to be addressed in the future.