Current Opinion in Genetics & Development最新文献

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.

A significant portion of the human proteome comprises RNA-binding proteins (RBPs) that play fundamental roles in numerous biological processes. In the last decade, there has been a staggering increase in RBP identification and classification, which has fueled interest in the evolving roles of RBPs and RBP-driven molecular mechanisms. Here, we focus on recent insights into RBP-dependent regulation of the epigenetic and transcriptional landscape. We describe advances in methodologies that define the RNA-protein interactome and machine-learning algorithms that are streamlining RBP discovery and predicting new RNA-binding regions. Finally, we present how RBP dysregulation leads to alterations in tumor-promoting gene expression and discuss the potential for targeting these RBPs for the development of new cancer therapeutics.

Epigenetic reprogramming during development is key to cell identity and the activities of the Polycomb repressive complexes are vital for this process. We focus on polycomb repressive complex 2 (PRC2), which catalyzes H3K27me1/2/3 and safeguards cellular integrity by ensuring proper gene repression. Notably, various accessory factors associate with PRC2, strongly influencing cell fate decisions, and their deregulation contributes to various illnesses. Yet, the exact role of these factors during development and carcinogenesis is not fully understood. Here, we present recent progress toward addressing these points and an analysis of the expression levels of PRC2 accessory factors in various tissues and developmental stages to highlight their abundance and roles. Last, we evaluate their contribution to cancer-specific phenotypes, providing insight into novel anticancer therapies.

Stem cell-based mammalian embryo models facilitate the discovery of developmental mechanisms because they are more amenable to genetic and epigenetic perturbations than natural embryos. Here, we highlight exciting recent advances that have yielded a plethora of models of embryonic development. Imperfections in these models highlight gaps in our current understanding and outline future research directions, ushering in an exciting new era for embryology.

Human development is a highly coordinated process, with any abnormalities during the early embryonic stages that can often have detrimental consequences. The complexity and nuances of human development underpin its significance in embryo research. However, this research is often hindered by limited availability and ethical considerations associated with the use of donated blastocysts from in vitro fertilization (IVF) surplus. Human blastoids offer promising alternatives as they can be easily generated and manipulated in the laboratory while preserving key characteristics of human blastocysts. In this way, they hold the potential to serve as a scalable and ethically permissible resource in embryology research. By utilizing such human embryo models, we can establish a transformative platform that complements the study with IVF embryos, ultimately enhancing our understanding of human embryogenesis.