Current Opinion in Genetics & Development最新文献

As the most well-studied modification in mRNA, m⁶A has been shown to regulate multiple biological processes, including RNA degradation, processing, and translation. Recent studies showed that m⁶A modification is enriched in chromatin-associated RNAs and nascent RNAs, suggesting m⁶A might play regulatory roles in chromatin contexts. Indeed, in the past several years, a number of studies have clarified how m⁶A and its modulators regulate different types of chromatin states. Specifically, in the past 2–3 years, several studies discovered the roles of m⁶A and/or its modulators in regulating constitutive and facultative heterochromatin, shedding interesting lights on RNA-dependent heterochromatin formation in mammalian cells. This review will summarize and discuss the mechanisms underlying m⁶A’s regulation in different types of heterochromatin, with a specific emphasis on the regulation in mammalian embryonic stem cells, which exhibit distinct features of multiple heterochromatin marks.

Recent work has shown that besides inducing fusion genes, structural variations (SVs) can also contribute to oncogenesis by disrupting the three-dimensional genome organization and dysregulating gene expression. At the chromatin-loop level, SVs can relocate enhancers or silencers from their original genomic loci to activate oncogenes or repress tumor suppressor genes. On a larger scale, different types of alterations in topologically associating domains (TADs) have been reported in cancer, such as TAD expansion, shuffling, and SV-induced neo-TADs. Furthermore, the transformation from normal cells to cancerous cells is usually coupled with active or repressive compartmental switches, and cancer-specific compartments have been proposed. This review discusses the sites, and the other latest advances in studying how SVs disrupt higher-order genome structure in cancer, which in turn leads to oncogene dysregulation. We also highlight the clinical implications of these changes and the challenges ahead in this field.

Genomes are organised through hierarchical structures, ranging from local kilobase-scale cis-regulatory contacts to large chromosome territories. Most notably, (sub)-compartments partition chromosomes according to transcriptional activity, while topologically associating domains (TADs) define cis-regulatory landscapes. The inactive X chromosome in mammals has provided unique insights into the regulation and function of the three-dimensional (3D) genome. Concurrent with silencing of the majority of genes and major alterations of its chromatin state, the X chromosome undergoes profound spatial rearrangements at multiple scales. These include the emergence of megadomains, alterations of the compartment structure and loss of the majority of TADs. Moreover, the Xist locus, which orchestrates X-chromosome inactivation, has provided key insights into regulation and function of regulatory domains. This review provides an overview of recent insights into the control of these structural rearrangements and contextualises them within a broader understanding of 3D genome organisation.

Temporal control is central to deploy and coordinate genetic programs during development. At present, there is limited understanding of the molecular mechanisms that govern the duration and speed of developmental processes. Timing mechanisms may run in parallel and/or interact with each other to integrate temporal signals throughout the organism. In this piece, we consider findings on the extrinsic control of developmental tempo and discuss the intrinsic roles of cell cycle, metabolic rates, protein turnover, and post-transcriptional mechanisms in the regulation of tempo during neural development.

Adenosine-to-inosine RNA editing, catalyzed by the enzymes ADAR1 and ADAR2, stands as a pervasive RNA modification. A primary function of ADAR1-mediated RNA editing lies in labeling endogenous double-stranded RNAs (dsRNAs) as ‘self’, thereby averting their potential to activate innate immune responses. Recent findings have highlighted additional roles of ADAR1, independent of RNA editing, that are crucial for immune control. Here, we focus on recent progress in understanding ADAR1’s RNA editing–dependent and –independent roles in immune control. We describe how ADAR1 regulates various dsRNA innate immune receptors through distinct mechanisms. Furthermore, we discuss the implications of ADAR1 and RNA editing in diseases, including autoimmune diseases and cancers.

Chromatin loops, which bring two distal loci of the same chromosome into close physical proximity, are the ubiquitous units of the three-dimensional genome. Recent advances in understanding the spatial organisation of chromatin suggest that several distinct mechanisms control chromatin interactions, such as loop extrusion by cohesin complexes, compartmentalisation by phase separation, direct protein–protein interactions and others. Here, we review different types of chromatin loops and highlight the factors and processes involved in their regulation. We discuss how loop extrusion and compartmentalisation shape chromatin interactions and how these two processes can either positively or negatively influence each other.

The human genome is not just a simple string of DNA, it is a complex and dynamic entity intricately folded within the cell’s nucleus. This three-dimensional organization of chromatin, the combination of DNA and proteins in the nucleus, is crucial for many biological processes and has been prominently studied for its intricate relationship to gene expression. Indeed, the transcriptional machinery does not operate in isolation but interacts intimately with the folded chromatin structure. Techniques for chromatin conformation capture, including genome-wide sequencing approaches, have revealed key organizational features of chromatin, such as the formation of loops by CCCTC-binding factor (CTCF) and the division of loci into chromatin compartments. While much of the recent research and reviews have focused on CTCF loops, we discuss several new revelations that have emerged concerning chromatin compartments, with a particular focus on what is known about mechanistic drivers of compartmentalization. These insights challenge the traditional views of chromatin organization and reveal the complexity behind the formation and maintenance of chromatin compartments.

Epigenetic priming presets chromatin states that allow the rapid induction of gene expression programs in response to differentiation cues. In the germline, it provides the blueprint for sexually dimorphic unidirectional differentiation. In this review, we focus on epigenetic priming in the mammalian male germline and discuss how cellular memories are regulated and inherited to the next generation. During spermatogenesis, epigenetic priming predetermines cellular memories that ensure the lifelong maintenance of spermatogonial stem cells and their subsequent commitment to meiosis and to the production of haploid sperm. The paternal chromatin state is also essential for the recovery of totipotency after fertilization and contributes to paternal epigenetic inheritance. Thus, epigenetic priming establishes stable but reversible chromatin states during spermatogenesis and enables epigenetic inheritance and reprogramming in the next generation.

Embryonic diapause in mammals is a period of developmental pause of the embryo at the blastocyst stage. During diapause, the blastocyst has minimal cell proliferation, metabolic activity and gene expression. At reactivation, blastocyst development resumes, characterised by increases in cell number, biosynthesis and metabolism. Until recently, it has been unknown how diapause is maintained without any loss of blastocyst viability. This review focuses on recent progress in the identification of molecular pathways occurring in the blastocyst that can both cause and maintain the diapause state. A switch to lipid metabolism now appears essential to maintaining the diapause state and is induced by forkhead box protein O1. The forkhead box protein O transcription family is important for diapause in insects, nematodes and fish, but this is the first time a conclusive role has been established in mammals. Multiple epigenetic modifications are also essential to inducing and maintaining the diapause state, including both DNA and RNA methylation mechanisms. Finally, it now appears that diapause embryos, dormant stem cells and chemotherapeutic-resistant cancer cells may all share a universal system of quiescence.

To make a multicellular organism, genes need to be transcribed at the right developmental stages and in the right tissues. DNA sequences termed ‘enhancers’ are crucial to achieve this. Despite concerted efforts, the exact mechanisms of enhancer activity remain elusive. Mixed lineage leukemia (MLL or KMT2A) rearrangements (MLLr), commonly observed in cases of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia, produce novel in-frame fusion proteins. Recent work has shown that the MLL-AF4 fusion protein drives aberrant enhancer activity at key oncogenes in ALL, dependent on the continued presence of MLL-AF4 complex components. As well as providing some general insights into enhancer function, these observations may also provide an explanation for transcriptional heterogeneity observed in MLLr patients.