Pub Date : 2024-11-22DOI: 10.1016/j.gde.2024.102282
Grace Bower, Evgeny Z Kvon
Enhancers are remotely located noncoding DNA sequences that regulate gene expression in response to developmental, homeostatic, and environmental cues. Canonical short-range enhancers located <50 kb from their cognate promoters function by binding transcription factors, coactivators, and chromatin modifiers. In this review, we discuss recent evidence that medium-range (50-400 kb) and long-range (>400 kb) enhancers rely on additional mechanisms, including cohesin, CCCTC-binding factor, and high-affinity protein-protein interactions. These mechanisms are crucial for establishing the physical proximity and interaction between enhancers and their target promoters over extended genomic distances and ensuring robust gene activation during mammalian development. Future studies will be critical to unravel their prevalence and evolutionary significance across various genomic loci, cell types, and species.
增强子是位置偏远的非编码 DNA 序列，可调节基因表达，对发育、同源性和环境线索做出反应。典型的短程增强子位于 400 kb）增强子依赖于其他机制，包括凝聚素、CCCTC 结合因子和高亲和性蛋白-蛋白相互作用。这些机制对于在较长的基因组距离内建立增强子与其目标启动子之间的物理邻近性和相互作用以及确保哺乳动物发育过程中基因的稳健激活至关重要。未来的研究对于揭示它们在不同基因组位点、细胞类型和物种中的普遍性和进化意义至关重要。
{"title":"Genetic factors mediating long-range enhancer-promoter communication in mammalian development.","authors":"Grace Bower, Evgeny Z Kvon","doi":"10.1016/j.gde.2024.102282","DOIUrl":"https://doi.org/10.1016/j.gde.2024.102282","url":null,"abstract":"<p><p>Enhancers are remotely located noncoding DNA sequences that regulate gene expression in response to developmental, homeostatic, and environmental cues. Canonical short-range enhancers located <50 kb from their cognate promoters function by binding transcription factors, coactivators, and chromatin modifiers. In this review, we discuss recent evidence that medium-range (50-400 kb) and long-range (>400 kb) enhancers rely on additional mechanisms, including cohesin, CCCTC-binding factor, and high-affinity protein-protein interactions. These mechanisms are crucial for establishing the physical proximity and interaction between enhancers and their target promoters over extended genomic distances and ensuring robust gene activation during mammalian development. Future studies will be critical to unravel their prevalence and evolutionary significance across various genomic loci, cell types, and species.</p>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"90 ","pages":"102282"},"PeriodicalIF":3.7,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.gde.2024.102280
Debashree Tagore, Joshua M Akey
As anatomically modern humans dispersed out of Africa, they encountered and mated with now extinct hominins, including Neanderthals and Denisovans. It is now well established that all non-African individuals derive approximately 2% of their genome from Neanderthal ancestors and individuals of Melanesian and Australian aboriginal ancestry inherited an additional 2%-5% of their genomes from Denisovan ancestors. Attention has started to shift from documenting amounts of archaic admixture and identifying introgressed segments to understanding their molecular, phenotypic, and evolutionary consequences and refining models of human history. Here, we review recent insights into admixture between modern and archaic humans, emphasizing methodological innovations and the functional and phenotypic effects Neanderthal and Denisovan sequences have in contemporary individuals.
{"title":"Archaic hominin admixture and its consequences for modern humans.","authors":"Debashree Tagore, Joshua M Akey","doi":"10.1016/j.gde.2024.102280","DOIUrl":"https://doi.org/10.1016/j.gde.2024.102280","url":null,"abstract":"<p><p>As anatomically modern humans dispersed out of Africa, they encountered and mated with now extinct hominins, including Neanderthals and Denisovans. It is now well established that all non-African individuals derive approximately 2% of their genome from Neanderthal ancestors and individuals of Melanesian and Australian aboriginal ancestry inherited an additional 2%-5% of their genomes from Denisovan ancestors. Attention has started to shift from documenting amounts of archaic admixture and identifying introgressed segments to understanding their molecular, phenotypic, and evolutionary consequences and refining models of human history. Here, we review recent insights into admixture between modern and archaic humans, emphasizing methodological innovations and the functional and phenotypic effects Neanderthal and Denisovan sequences have in contemporary individuals.</p>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"90 ","pages":"102280"},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1016/j.gde.2024.102277
Patrick O Nnoromele , McKaily Adams , Annabelle Pan , Ying V Liu , Joyce Wang , Mandeep S Singh
The transplantation of human organoid-derived retinal cells is being studied as a potentially viable strategy to treat vision loss due to retinal degeneration. Experiments in animal models have demonstrated the feasibility of organoid-derived photoreceptor transplantation in various recipient contexts. In some cases, vision repair has been shown. However, recipient–donor cell–cell interactions are incompletely understood. This review briefly summarizes these interactions, categorizing them as synaptic structure formation, cellular component transfer, glial activation, immune cell infiltration, and cellular migration. Each of these interactions may affect the survival and functionality of the donor cells and, ultimately, their efficacy as a treatment substrate. Additionally, recipient characteristics, such as the cytoarchitecture of the retina and immune status, may also impact the type and frequency of cell–cell interactions. Despite the procedural challenges associated with culturing human retinal organoids and the technical difficulties in transplanting donor cells into the delicate recipient retina, transplantation of retinal organoid-derived cells is a promising tool for degenerative retinal disease treatment.
{"title":"Cell–cell interactions between transplanted retinal organoid cells and recipient tissues","authors":"Patrick O Nnoromele , McKaily Adams , Annabelle Pan , Ying V Liu , Joyce Wang , Mandeep S Singh","doi":"10.1016/j.gde.2024.102277","DOIUrl":"10.1016/j.gde.2024.102277","url":null,"abstract":"<div><div>The transplantation of human organoid-derived retinal cells is being studied as a potentially viable strategy to treat vision loss due to retinal degeneration. Experiments in animal models have demonstrated the feasibility of organoid-derived photoreceptor transplantation in various recipient contexts. In some cases, vision repair has been shown. However, recipient–donor cell–cell interactions are incompletely understood. This review briefly summarizes these interactions, categorizing them as synaptic structure formation, cellular component transfer, glial activation, immune cell infiltration, and cellular migration. Each of these interactions may affect the survival and functionality of the donor cells and, ultimately, their efficacy as a treatment substrate. Additionally, recipient characteristics, such as the cytoarchitecture of the retina and immune status, may also impact the type and frequency of cell–cell interactions. Despite the procedural challenges associated with culturing human retinal organoids and the technical difficulties in transplanting donor cells into the delicate recipient retina, transplantation of retinal organoid-derived cells is a promising tool for degenerative retinal disease treatment.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"89 ","pages":"Article 102277"},"PeriodicalIF":3.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1016/j.gde.2024.102278
Nicole D Moss , Davoneshia Lollis , Debra L Silver
Understanding what makes us uniquely human is a long-standing question permeating fields from genomics, neuroscience, and developmental biology to medicine. The discovery of human-specific genomic sequences has enabled a new understanding of the molecular features of human brain evolution. Advances in sequencing, computational, and in vitro screening approaches collectively reveal new roles of uniquely human sequences in regulating gene expression. Here, we review the landscape of human-specific loci and describe how emerging technologies are being used to understand their molecular functions and impact on brain development. We describe current challenges in the field and the potential of integrating new hypotheses and approaches to propel our understanding of the human brain.
{"title":"How our brains are built: emerging approaches to understand human-specific features","authors":"Nicole D Moss , Davoneshia Lollis , Debra L Silver","doi":"10.1016/j.gde.2024.102278","DOIUrl":"10.1016/j.gde.2024.102278","url":null,"abstract":"<div><div>Understanding what makes us uniquely human is a long-standing question permeating fields from genomics, neuroscience, and developmental biology to medicine. The discovery of human-specific genomic sequences has enabled a new understanding of the molecular features of human brain evolution. Advances in sequencing, computational, and <em>in vitro</em> screening approaches collectively reveal new roles of uniquely human sequences in regulating gene expression. Here, we review the landscape of human-specific loci and describe how emerging technologies are being used to understand their molecular functions and impact on brain development. We describe current challenges in the field and the potential of integrating new hypotheses and approaches to propel our understanding of the human brain.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"89 ","pages":"Article 102278"},"PeriodicalIF":3.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1016/j.gde.2024.102275
Yunlong Y Jia , Scott X Atwood
Recently, significant strides have been made in the development of high-fidelity skin organoids, encompassing techniques such as 3D bioprinting, skin-on-a-chip systems, and models derived from pluripotent stem cells (PSCs), replicating appendage structures and diverse skin cell types. Despite the emergence of these state-of-the-art skin engineering models, human organotypic cultures (OTCs), initially proposed in the 1970s, continue to reign as the predominant in vitro cultured three-dimensional skin model in the field of tissue engineering. This enduring prevalence is owed to their cost-effectiveness, straight forward setup, time efficiency, and faithful representation of native human skin. In this review, we systematically delineate recent advances in skin OTC models, aiming to inform future efforts to enhance in vitro skin model fidelity and reproducibility.
{"title":"Diversity of human skin three-dimensional organotypic cultures","authors":"Yunlong Y Jia , Scott X Atwood","doi":"10.1016/j.gde.2024.102275","DOIUrl":"10.1016/j.gde.2024.102275","url":null,"abstract":"<div><div>Recently, significant strides have been made in the development of high-fidelity skin organoids, encompassing techniques such as 3D bioprinting, skin-on-a-chip systems, and models derived from pluripotent stem cells (PSCs), replicating appendage structures and diverse skin cell types. Despite the emergence of these state-of-the-art skin engineering models, human organotypic cultures (OTCs), initially proposed in the 1970s, continue to reign as the predominant <em>in vitro</em> cultured three-dimensional skin model in the field of tissue engineering. This enduring prevalence is owed to their cost-effectiveness, straight forward setup, time efficiency, and faithful representation of native human skin. In this review, we systematically delineate recent advances in skin OTC models, aiming to inform future efforts to enhance <em>in vitro</em> skin model fidelity and reproducibility.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"89 ","pages":"Article 102275"},"PeriodicalIF":3.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-06DOI: 10.1016/j.gde.2024.102276
Sefali Patel , Wen Liu , Ravikumar K , Catherine McCormick , Yong Fan
Recent advances in immunotherapy have underscored the potential of harnessing the immune system to treat disorders associated with immune dysregulation, such as primary and secondary immunodeficiencies, cancer, transplantation rejection, and aging. Owing to the cellular and structural complexity and the dynamic nature of immune responses, engineering immune organoids that replicate the function and key features of their corresponding immune organs continues to be a formidable challenge. In this overview, we will discuss the recent progress in bioengineering organoids of key primary and secondary immune organs and tissues, focusing particularly on their contributions to the host’s immune system in animal models and highlighting their potential roles in regenerative medicine.
{"title":"Engineering immune organoids to regenerate host immune system","authors":"Sefali Patel , Wen Liu , Ravikumar K , Catherine McCormick , Yong Fan","doi":"10.1016/j.gde.2024.102276","DOIUrl":"10.1016/j.gde.2024.102276","url":null,"abstract":"<div><div>Recent advances in immunotherapy have underscored the potential of harnessing the immune system to treat disorders associated with immune dysregulation, such as primary and secondary immunodeficiencies, cancer, transplantation rejection, and aging. Owing to the cellular and structural complexity and the dynamic nature of immune responses, engineering immune organoids that replicate the function and key features of their corresponding immune organs continues to be a formidable challenge. In this overview, we will discuss the recent progress in bioengineering organoids of key primary and secondary immune organs and tissues, focusing particularly on their contributions to the host’s immune system in animal models and highlighting their potential roles in regenerative medicine.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"89 ","pages":"Article 102276"},"PeriodicalIF":3.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142593216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-05DOI: 10.1016/j.gde.2024.102274
Charis Fountas, Tineke L Lenstra
Transcriptional bursting refers to the stochastic transition of a promoter between transcriptionally active and inactive states. This dynamic process is highly regulated by the dynamics of transcription factor binding to DNA, their interactions with coactivators, and the 3D interactions between promoters, condensates, and enhancers. In this mini-review, we discuss recent insights into the kinetics of transcription factors and cofactors in both simple and complex regulatory environments to understand their impact on transcriptional bursting. We examine the novel concept of transcription factor exchange and relate it to different cooperativity models. Finally, we discuss recent live-cell imaging studies on the regulation of transcriptional bursting by enhancers and transcriptional condensates.
转录猝发是指启动子在转录活跃和不活跃状态之间的随机转换。这一动态过程受到转录因子与 DNA 结合的动态、转录因子与辅助激活因子的相互作用以及启动子、凝聚子和增强子之间的三维相互作用的高度调控。在这篇微型综述中，我们将讨论转录因子和辅助因子在简单和复杂调控环境中的动力学最新见解，以了解它们对转录猝发的影响。我们研究了转录因子交换的新概念，并将其与不同的合作性模型联系起来。最后，我们讨论了最近关于增强子和转录凝聚物调控转录突变的活细胞成像研究。
{"title":"Better together: how cooperativity influences transcriptional bursting","authors":"Charis Fountas, Tineke L Lenstra","doi":"10.1016/j.gde.2024.102274","DOIUrl":"10.1016/j.gde.2024.102274","url":null,"abstract":"<div><div>Transcriptional bursting refers to the stochastic transition of a promoter between transcriptionally active and inactive states. This dynamic process is highly regulated by the dynamics of transcription factor binding to DNA, their interactions with coactivators, and the 3D interactions between promoters, condensates, and enhancers. In this mini-review, we discuss recent insights into the kinetics of transcription factors and cofactors in both simple and complex regulatory environments to understand their impact on transcriptional bursting. We examine the novel concept of transcription factor exchange and relate it to different cooperativity models. Finally, we discuss recent live-cell imaging studies on the regulation of transcriptional bursting by enhancers and transcriptional condensates.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"89 ","pages":"Article 102274"},"PeriodicalIF":3.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.gde.2024.102272
Jonathan C Schmok , Gene W Yeo
Alternative splicing (AS) plays a pivotal role in protein diversity and mRNA maturation. Programmable control of targeted AS events is of longstanding interest in RNA biology, promising correction of dysregulated splicing in disease and discovery of AS events. This review explores four main strategies for programmable splicing manipulation: (1) inhibiting splicing signals with antisense oligonucleotides (ASOs), exemplified by therapies approved by the U.S. Food and Drug Administration, (2) applying DNA-targeting clustered regularly interspaced short palindromic repeats systems to edit splicing signals, (3) using synthetic splicing factors, including synthetic proteins and ribonucleoproteins, inspired by natural RNA-binding proteins, and (4) guiding endogenous splicing machinery with bifunctional ASOs and engineered small nuclear RNAs. While ASOs remain clinically prominent, emerging technologies aim for broad, scalable, durable, and precise splicing modulation, holding promise for transformative advancements in RNA biology and therapeutic interventions.
替代剪接（AS）在蛋白质多样性和 mRNA 成熟中起着关键作用。可编程控制目标 AS 事件是 RNA 生物学长期关注的问题，有望纠正疾病中的剪接失调并发现 AS 事件。本综述探讨了可编程剪接操作的四种主要策略：（1）用反义寡核苷酸（ASO）抑制剪接信号，美国食品药品管理局批准的疗法就是一例；（2）用反义寡核苷酸抑制剪接信号，美国食品药品管理局批准的疗法是一例；（3）用反义寡核苷酸抑制剪接信号，美国食品药品管理局批准的疗法是一例；（4）用反义寡核苷酸抑制剪接信号，美国食品药品管理局批准的疗法是一例。美国食品和药物管理局批准的疗法就是一例；(2) 利用 DNA 靶向簇状规则间隔短回文重复序列系统编辑剪接信号；(3) 利用合成剪接因子，包括受天然 RNA 结合蛋白启发的合成蛋白和核糖核蛋白；(4) 利用双功能 ASO 和工程化小核 RNA 引导内源性剪接机制。虽然 ASO 在临床上仍很突出，但新兴技术旨在实现广泛、可扩展、持久和精确的剪接调控，有望在 RNA 生物学和治疗干预方面取得变革性进展。
{"title":"Strategies for programmable manipulation of alternative splicing","authors":"Jonathan C Schmok , Gene W Yeo","doi":"10.1016/j.gde.2024.102272","DOIUrl":"10.1016/j.gde.2024.102272","url":null,"abstract":"<div><div>Alternative splicing (AS) plays a pivotal role in protein diversity and mRNA maturation. Programmable control of targeted AS events is of longstanding interest in RNA biology, promising correction of dysregulated splicing in disease and discovery of AS events. This review explores four main strategies for programmable splicing manipulation: (1) inhibiting splicing signals with antisense oligonucleotides (ASOs), exemplified by therapies approved by the U.S. Food and Drug Administration, (2) applying DNA-targeting clustered regularly interspaced short palindromic repeats systems to edit splicing signals, (3) using synthetic splicing factors, including synthetic proteins and ribonucleoproteins, inspired by natural RNA-binding proteins, and (4) guiding endogenous splicing machinery with bifunctional ASOs and engineered small nuclear RNAs. While ASOs remain clinically prominent, emerging technologies aim for broad, scalable, durable, and precise splicing modulation, holding promise for transformative advancements in RNA biology and therapeutic interventions.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"89 ","pages":"Article 102272"},"PeriodicalIF":3.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1016/j.gde.2024.102271
François Fuks , Michael Kharas
{"title":"Editorial overview: Epitranscriptomics: Exploring a new frontier in health and disease","authors":"François Fuks , Michael Kharas","doi":"10.1016/j.gde.2024.102271","DOIUrl":"10.1016/j.gde.2024.102271","url":null,"abstract":"","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"89 ","pages":"Article 102271"},"PeriodicalIF":3.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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