Current Opinion in Genetics & Development最新文献

Evolution of the cerebral cortex is thought to have been critical for the emergence of our cognitive abilities. Major features of cortical evolution include increased neuron number and connectivity and altered morpho-electric properties of cortical neurons. Significant progress has been made in identifying human-specific genetic modifiers (HSGMs), some of which are involved in shaping these features of cortical architecture. But how did these evolutionary changes support the emergence of our cognitive abilities? Here, we highlight recent studies aimed at examining the impact of HSGMs on cortical circuit function and behavior. We also discuss the need for greater insight into the link between evolution of cortical architecture and the functional and computational properties of neuronal circuits, as we seek to provide a neurobiological foundation for human cognition.

N⁶-methyladenosine (m⁶A) is the most abundant internal modification of eukaryotic mRNAs. m⁶A affects the fate of its targets in all aspects of the mRNA life cycle and has important roles in various physiological and pathophysiological processes. Aberrant m⁶A patterns have been observed in numerous cancers and appear closely linked to oncogenic phenotypes. However, most studies relied on antibody-dependent modification detection, which is known to suffer from important limitations. Novel, antibody-independent, quantitative approaches will be critical to investigate changes in the m⁶A landscape of cancers. Furthermore, pharmaceutical targeting of the m⁶A writer Methyltransferase-like 3 (METTL3) has demonstrated the potential to modulate cancer cell phenotypes. However, the enzyme also appears to be essential for the viability of healthy cells. Further refinement of therapeutic strategies is therefore needed to fully realize the potential of m⁶A-related cancer therapies.

The aim of regenerative medicine is to restore specific functions to damaged cells or tissues. A crucial aspect of success lies in effectively reintegrating these cells or tissues within the recipient organism. This is particularly pertinent for diabetes, where islet function relies on the close connection of beta cells to the bloodstream for glucose sensing and insulin release. Central to this approach is the need to establish a fast connection with the host’s vascular system. In this review, we explore the intricate relationships between endocrine, vascular, and immune cell interactions in transplantation outcomes. We also delve into recent strategies aimed at enhancing engraftment, along with the utilization of in vitro platforms to model cellular interactions.

Structural variants (SVs) account for the majority of base pair differences both within and between primate species. However, our understanding of inter- and intra-species SV has been historically hampered by the quality of draft primate genomes and the absence of genome resources for key taxa. Recently, advances in long-read sequencing and genome assembly have begun to radically reshape our understanding of SVs. Two landmark achievements include the publication of a human telomere-to-telomere (T2T) genome as well as the development of the first human pangenome reference. In this review, we first look back to the major works laying the foundation for these projects. We then examine the ways in which T2T genome assemblies and pangenomes are transforming our understanding of and approach to primate SV. Finally, we discuss what the future of primate SV research may look like in the era of T2T genomes and pangenomics.

The human brain is composed of increasingly recognized heterogeneous cell types. Applying single-cell genomics to brain tissue can elucidate relative cell type proportions as well as differential gene expression and regulation among humans and other species. Here, we review recent studies that utilized high-throughput genomics approaches to compare brains among species at single-cell resolution. These studies identified genomic elements that are similar among species as well as evolutionary novelties on the human lineage. We focus on those human-relevant innovations and discuss the biological implications of these modifications. Finally, we discuss areas of comparative single-cell genomics that remain unexplored either due to needed technological advances or due to biological availability at the brain region or species level.

Understanding the development and function of the human neuromuscular system is crucial for deciphering the mechanisms of neuromuscular disorders and developing effective therapies. However, limitations of animal models necessitate the development of human-specific in vitro models to study such complex diseases effectively. Here, we discuss different approaches for in vitro neuromuscular junction (NMJ) modeling: complex self-organized models that rely on the inherent abilities of cells to form NMJs based on embryonic developmental principles and assembled models that depend on integrating different cell types for controlled NMJ formation. Finally, we discuss the advantages and limitations of these models and the need for continued advancements enhanced by bioengineering approaches to deepen our understanding of human NMJ biology and pave the way for personalized medicine.

Precise temporal and sequential control of gene expression during development and in response to environmental stimuli requires tight regulation of the physical contact between gene regulatory elements and promoters. Current models describing how the genome folds in 3D space to establish these interactions often ignore the role of the most stable structural nuclear feature — the nuclear envelope. While contributions of 3D folding within/between topologically associated domains (TADs) have been extensively described, mechanical contributions from the nuclear envelope can impact enhancer–promoter interactions both directly and indirectly through influencing intra/inter-TAD interactions. Importantly, these nuclear envelope contributions clearly link this mechanism to development and, when defective, to human disease. Here, we discuss evidence for nuclear envelope regulation of tissue-specific enhancer–promoter pairings, potential mechanisms for this regulation, exciting recent findings that other regulatory elements such as microRNAs and long noncoding RNAs are under nuclear envelope regulation, the possible involvement of condensates, and how disruption of this regulation can lead to disease.

The epitranscriptome encompasses over 170 post-transcriptional modifications found in various RNA species. RNA modifications play pivotal roles in regulating gene expression by shaping RNA structure and function, implicating the epitranscriptome in diverse biological processes, including pathology progression. This review focuses on research elucidating the roles of the epitranscriptome in cancer metastasis. Metastasis, a primary cause of solid tumor patient mortality, involves a multistep process whereby tumor cells migrate from a primary tumor to distant secondary organs. We discuss RNA modifications found on rRNA, tRNA, and mRNA, highlighting their roles in different stages of metastasis. Understanding mechanisms by which modifications regulate molecular and cellular processes during metastasis is crucial for leveraging epitranscriptomic signatures in cancer diagnosis and treatment.

Regenerative capacities and strategies vary dramatically across animals, as well as between cell types, organs, and with age. In recent years, high-throughput single-cell transcriptomics and other single-cell profiling technologies have been applied to many animal models to gain an understanding of the cellular and molecular mechanisms underlying regeneration. Here, we review recent single-cell studies of regeneration in diverse contexts and summarize key concepts that have emerged. The immense regenerative capacity of some invertebrates, exemplified by planarians, is driven mainly by the differentiation of abundant adult pluripotent stem cells, whereas in many other cases, regeneration involves the reactivation of embryonic or developmental gene-regulatory networks in differentiated cell types. However, regeneration also differs from development in many ways, including the use of regeneration-specific cell types and gene regulatory networks.

To regulate gene expression, the macromolecular components of the mammalian interphase nucleus are spatially organized into a myriad of functional compartments. Over the past decade, increasingly sophisticated genomics, microscopy, and functional approaches have probed this organization in unprecedented detail. These investigations have linked chromatin-associated noncoding RNAs to specific nuclear compartments and uncovered mechanisms by which these RNAs establish such domains. In this review, we focus on the long non-coding RNA Xist and summarize new evidence demonstrating the significance of chromatin reconfiguration in creating the inactive X-chromosome compartment. Differences in chromatin compaction correlate with distinct levels of gene repression on the X-chromosome, potentially explaining how human XIST can induce chromosome-wide dampening and silencing of gene expression at different stages of human development.