Pub Date : 2026-01-14DOI: 10.1016/j.gde.2025.102429
Shuvadip Dutta , Ranjith Padinhateeri
Polymer physics-based models of chromatin are essential for interpreting experimental observations and gaining mechanistic insights into genome organization and its functional consequences. However, because chromatin is a highly complex polymer, its fundamental physical properties remain poorly understood. Deriving these properties from experiments and using them to simulate chromatin behavior and predict functional outcomes remain key challenges in the field. Another major challenge is to understand how ATP-dependent active forces act along the genome and to incorporate these effects into models of chromatin dynamics. In this review, we discuss recent advances that address these challenges and highlight the strengths, limitations, and predictive capabilities of current modeling approaches for studying interphase chromatin.
{"title":"Polymer simulations of chromatin: connecting 3D organization and dynamics to function","authors":"Shuvadip Dutta , Ranjith Padinhateeri","doi":"10.1016/j.gde.2025.102429","DOIUrl":"10.1016/j.gde.2025.102429","url":null,"abstract":"<div><div>Polymer physics-based models of chromatin are essential for interpreting experimental observations and gaining mechanistic insights into genome organization and its functional consequences. However, because chromatin is a highly complex polymer, its fundamental physical properties remain poorly understood. Deriving these properties from experiments and using them to simulate chromatin behavior and predict functional outcomes remain key challenges in the field. Another major challenge is to understand how ATP-dependent active forces act along the genome and to incorporate these effects into models of chromatin dynamics. In this review, we discuss recent advances that address these challenges and highlight the strengths, limitations, and predictive capabilities of current modeling approaches for studying interphase chromatin.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102429"},"PeriodicalIF":3.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978553","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 : 2026-01-14DOI: 10.1016/j.gde.2025.102428
Yuzhi Bao , Shaoqian Ma , Xiaohua Shen , Lennart Hilbert
Stem cells display a highly dispersed genome organization that supports flexible gene regulation. Here, we present block copolymer concepts to explore how transcriptional activity from specific genomic regions, or ‘blocks’, shapes and controls several features of this architecture. Nascent transcripts tethered to chromatin can disrupt compaction and promote the formation of a micro-dispersed state of euchromatin, explaining one typical feature of the stem cell genome. A second feature is long-lived transcriptional clusters, which form via condensation at super-enhancer blocks and mediate both long-range interactions and local transcription factor accumulation. Lastly, we conceptualize promoters and gene bodies as a two-block polymer, for which sequential switching on and off of the polymer blocks controls the association and subsequent release of developmental genes with the long-lived clusters. The presented block copolymer framework provides explanations as well as hypotheses of how transcription-associated processes contribute to distinct features of stem cell genome organization.
{"title":"Block copolymer concepts of how transcription organizes the stem cell genome","authors":"Yuzhi Bao , Shaoqian Ma , Xiaohua Shen , Lennart Hilbert","doi":"10.1016/j.gde.2025.102428","DOIUrl":"10.1016/j.gde.2025.102428","url":null,"abstract":"<div><div>Stem cells display a highly dispersed genome organization that supports flexible gene regulation. Here, we present block copolymer concepts to explore how transcriptional activity from specific genomic regions, or ‘blocks’, shapes and controls several features of this architecture. Nascent transcripts tethered to chromatin can disrupt compaction and promote the formation of a micro-dispersed state of euchromatin, explaining one typical feature of the stem cell genome. A second feature is long-lived transcriptional clusters, which form via condensation at super-enhancer blocks and mediate both long-range interactions and local transcription factor accumulation. Lastly, we conceptualize promoters and gene bodies as a two-block polymer, for which sequential switching on and off of the polymer blocks controls the association and subsequent release of developmental genes with the long-lived clusters. The presented block copolymer framework provides explanations as well as hypotheses of how transcription-associated processes contribute to distinct features of stem cell genome organization.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102428"},"PeriodicalIF":3.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978554","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 : 2026-01-13DOI: 10.1016/j.gde.2025.102431
Ashlesha Gogate , Maria H Chahrour
Neurogenomics has provided exceptional insights into the genetic architecture underlying autism spectrum disorder (ASD), which is increasingly understood as a collection of individually rare disorders. This review synthesizes current advancements in the field, examining how both rare and common genetic variants contribute to ASD etiology. To functionally interpret the convergence on biological pathways that has emerged despite this genetic heterogeneity, multiomic approaches have been applied to identify gene regulatory networks disrupted in ASD. High-throughput technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR) editing and massively parallel reporter assays, have been employed in human induced pluripotent stem cells and organoids to bridge the gap between genetic association and biological function. Finally, machine learning methods play a pivotal role in integrating and leveraging these complex datasets to inform personalized interventions.
{"title":"Recent advances in the neurogenomics of autism spectrum disorder","authors":"Ashlesha Gogate , Maria H Chahrour","doi":"10.1016/j.gde.2025.102431","DOIUrl":"10.1016/j.gde.2025.102431","url":null,"abstract":"<div><div>Neurogenomics has provided exceptional insights into the genetic architecture underlying autism spectrum disorder (ASD), which is increasingly understood as a collection of individually rare disorders. This review synthesizes current advancements in the field, examining how both rare and common genetic variants contribute to ASD etiology. To functionally interpret the convergence on biological pathways that has emerged despite this genetic heterogeneity, multiomic approaches have been applied to identify gene regulatory networks disrupted in ASD. High-throughput technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR) editing and massively parallel reporter assays, have been employed in human induced pluripotent stem cells and organoids to bridge the gap between genetic association and biological function. Finally, machine learning methods play a pivotal role in integrating and leveraging these complex datasets to inform personalized interventions.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102431"},"PeriodicalIF":3.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978552","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 : 2026-01-12DOI: 10.1016/j.gde.2025.102430
Sinem Erkan , Kalyan Ghadage , Peter Meister
Genome folding is a key regulator of transcription, chromosome segregation, and genome stability. In Caenorhabditis elegans, chromatin folding strategies have diverged from those observed in mammals or flies, resulting in the absence of visible topologically associating domains (TADs) on autosomes. Here, condensin I, rather than cohesin, serves as the primary long-range loop extruder, while distinct cohesin isoforms specialize in mitotic cohesion and loop extrusion, forming enhancer-associated ‘fountains’ that modulate neuronal gene expression. On the X chromosome, dosage compensation depends on the dosage compensation complex, which incorporates a specialized condensin IDC to establish TADs, regulate chromatin states, and repress transcription. These multilayered mechanisms illustrate the evolutionary versatility of 3D genome organization and its intimate links to development, physiology, and lifespan, positioning C. elegans as a powerful model for dissecting structural maintenance of chromosomes–mediated genome regulation.
{"title":"Chromosome organization by Structural Maintenance of Chromosomes complexes in C. elegans","authors":"Sinem Erkan , Kalyan Ghadage , Peter Meister","doi":"10.1016/j.gde.2025.102430","DOIUrl":"10.1016/j.gde.2025.102430","url":null,"abstract":"<div><div>Genome folding is a key regulator of transcription, chromosome segregation, and genome stability. In <em>Caenorhabditis elegans</em>, chromatin folding strategies have diverged from those observed in mammals or flies, resulting in the absence of visible topologically associating domains (TADs) on autosomes. Here, condensin I, rather than cohesin, serves as the primary long-range loop extruder, while distinct cohesin isoforms specialize in mitotic cohesion and loop extrusion, forming enhancer-associated ‘fountains’ that modulate neuronal gene expression. On the X chromosome, dosage compensation depends on the dosage compensation complex, which incorporates a specialized condensin I<sup>DC</sup> to establish TADs, regulate chromatin states, and repress transcription. These multilayered mechanisms illustrate the evolutionary versatility of 3D genome organization and its intimate links to development, physiology, and lifespan, positioning <em>C. elegans</em> as a powerful model for dissecting structural maintenance of chromosomes–mediated genome regulation.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102430"},"PeriodicalIF":3.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145967729","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 : 2026-01-10DOI: 10.1016/j.gde.2025.102427
Deevitha Balasubramanian , Margarita Masoura , Yad Ghavi-Helm
Transcription is classically known to be regulated by two key elements, promoters and enhancers. While these remain central to gene regulation, it is now clear that additional regulatory sequences fine-tune enhancer function and transcriptional output. In this review, we focus on two such recently described sequences, promoter-proximal elements and enhancer-like modulators, highlighting representative examples of their function and their proposed mechanisms of action. We further discuss the implications of these discoveries on the current definitions of promoters and enhancers, and highlight an emerging theme that such elements do not fall into discrete classes but instead function along a regulatory continuum. Recognizing this continuum and appreciating transcriptional control as an interconnected network of elements will be essential for understanding gene regulation in complex genomes.
{"title":"Cooperativity between regulatory elements acts as a modulator of enhancer function","authors":"Deevitha Balasubramanian , Margarita Masoura , Yad Ghavi-Helm","doi":"10.1016/j.gde.2025.102427","DOIUrl":"10.1016/j.gde.2025.102427","url":null,"abstract":"<div><div>Transcription is classically known to be regulated by two key elements, promoters and enhancers. While these remain central to gene regulation, it is now clear that additional regulatory sequences fine-tune enhancer function and transcriptional output. In this review, we focus on two such recently described sequences, promoter-proximal elements and enhancer-like modulators, highlighting representative examples of their function and their proposed mechanisms of action. We further discuss the implications of these discoveries on the current definitions of promoters and enhancers, and highlight an emerging theme that such elements do not fall into discrete classes but instead function along a regulatory continuum. Recognizing this continuum and appreciating transcriptional control as an interconnected network of elements will be essential for understanding gene regulation in complex genomes.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102427"},"PeriodicalIF":3.6,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145927353","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 : 2026-01-08DOI: 10.1016/j.gde.2025.102425
Sebastian H Heesen , Man-Hsin Chang , Michael C Wehr , Moritz J Rossner
The success of comprehensive genome-wide association studies has substantiated the multigenetic origin of most mental disorders, including schizophrenia, bipolar disorder, and major depression. Non-coding genetic variants are enriched mainly in regulatory regions of genes expressed in excitatory and inhibitory neurons and converge particularly on cellular pathways implicated in neurodevelopment and synaptic functions. Given the molecular and cellular complexity of mental disorders, classical ‘single-drug-target-based’ drug discovery has largely failed in delivering novel pharmacological treatment options. We believe that drug development for complex disorders requires a paradigm shift toward a ‘phenotype or pathway focused’ approach, which integrates multi-parametric assay technologies and stem technology to perform screening and lead compound validation with dramatically enhanced contextual specificity. Moreover, many existing drugs used to treat mental disorders display polypharmacological actions. Therefore, there is a demand for developing assay technologies capable of dissecting the complex modes of action of novel drug candidates in a cost-effective manner. Here, we review technological progress across various fields that hold promise in delivering future breakthrough treatments for mental disorders.
{"title":"Revitalizing psychopharmacology in the GWAS era: the potential of barcoded screening in drug discovery","authors":"Sebastian H Heesen , Man-Hsin Chang , Michael C Wehr , Moritz J Rossner","doi":"10.1016/j.gde.2025.102425","DOIUrl":"10.1016/j.gde.2025.102425","url":null,"abstract":"<div><div>The success of comprehensive genome-wide association studies has substantiated the multigenetic origin of most mental disorders, including schizophrenia, bipolar disorder, and major depression. Non-coding genetic variants are enriched mainly in regulatory regions of genes expressed in excitatory and inhibitory neurons and converge particularly on cellular pathways implicated in neurodevelopment and synaptic functions. Given the molecular and cellular complexity of mental disorders, classical ‘single-drug-target-based’ drug discovery has largely failed in delivering novel pharmacological treatment options. We believe that drug development for complex disorders requires a paradigm shift toward a ‘phenotype or pathway focused’ approach, which integrates multi-parametric assay technologies and stem technology to perform screening and lead compound validation with dramatically enhanced contextual specificity. Moreover, many existing drugs used to treat mental disorders display polypharmacological actions. Therefore, there is a demand for developing assay technologies capable of dissecting the complex modes of action of novel drug candidates in a cost-effective manner. Here, we review technological progress across various fields that hold promise in delivering future breakthrough treatments for mental disorders.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102425"},"PeriodicalIF":3.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145927354","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 : 2026-01-08DOI: 10.1016/j.gde.2025.102426
Giada Forte , Chris A. Brackley , Nick Gilbert , Davide Marenduzzo
The cell nucleus is a dynamic environment where ATP-driven processes — like transcription, replication, and epigenetic modifications — continually drive the genome far from thermodynamic equilibrium. Recent interdisciplinary efforts combining cell biology and physics have introduced coarse-grained polymer models that reveal how these active processes shape chromosome organization in space and time. We review how these models have shed light on selected key features of nuclear function: the maintenance of epigenetic memory, the coupling between transcriptional activity and chromatin motion, and the emergence of replication factories. These approaches provide mechanistic insight and predictive power that are beyond experiments alone. We conclude by outlining future directions toward viewing the genome as an active polymer maintained far from equilibrium.
{"title":"Nonequilibrium polymer models for chromatin","authors":"Giada Forte , Chris A. Brackley , Nick Gilbert , Davide Marenduzzo","doi":"10.1016/j.gde.2025.102426","DOIUrl":"10.1016/j.gde.2025.102426","url":null,"abstract":"<div><div>The cell nucleus is a dynamic environment where ATP-driven processes — like transcription, replication, and epigenetic modifications — continually drive the genome far from thermodynamic equilibrium. Recent interdisciplinary efforts combining cell biology and physics have introduced coarse-grained polymer models that reveal how these active processes shape chromosome organization in space and time. We review how these models have shed light on selected key features of nuclear function: the maintenance of epigenetic memory, the coupling between transcriptional activity and chromatin motion, and the emergence of replication factories. These approaches provide mechanistic insight and predictive power that are beyond experiments alone. We conclude by outlining future directions toward viewing the genome as an active polymer maintained far from equilibrium.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102426"},"PeriodicalIF":3.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145927355","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 : 2025-12-29DOI: 10.1016/j.gde.2025.102424
Tuo Shi , Xin Jin
Although there are many known risk alleles associated with adult-onset psychiatric disorders such as schizophrenia [1–4], bipolar disorder [5–7], and major depressive disorder [8−10], the mechanistic links between these risk alleles and disease pathology, especially on a circuit-level, remain unclear. In vivo pooled CRISPR screening with single‑cell readout (in vivo Perturb‑seq) has begun to fill this gap by mapping causal genes to defined cell states directly in animal tissues [11–14]. Here, we review recent developments and applications of in vivo Perturb-seq in the mouse brain and highlight the potential of utilizing human cellular systems to extend these approaches. Additionally, we discuss how in vivo Perturb-seq can couple genetic perturbation with physiological or environmental perturbations to better model psychiatric diseases with environmental triggers.
虽然有许多已知的风险等位基因与成人发病的精神疾病相关，如精神分裂症[1-4]、双相情感障碍[5-7]和重度抑郁症[8-10]，但这些风险等位基因与疾病病理之间的机制联系，特别是在回路水平上，仍不清楚。利用单细胞读数（In vivo Perturb - seq）在体内汇集CRISPR筛选已经开始填补这一空白，通过直接在动物组织中将致病基因定位到确定的细胞状态[11-14]。在这里，我们回顾了体内Perturb-seq在小鼠大脑中的最新发展和应用，并强调了利用人类细胞系统扩展这些方法的潜力。此外，我们讨论了体内扰动序列如何将遗传扰动与生理或环境扰动耦合起来，以更好地模拟具有环境触发因素的精神疾病。
{"title":"Probing neuropsychiatric disorders through in vivo CRISPR screening","authors":"Tuo Shi , Xin Jin","doi":"10.1016/j.gde.2025.102424","DOIUrl":"10.1016/j.gde.2025.102424","url":null,"abstract":"<div><div>Although there are many known risk alleles associated with adult-onset psychiatric disorders such as schizophrenia [1–4], bipolar disorder [5–7], and major depressive disorder [8−10], the mechanistic links between these risk alleles and disease pathology, especially on a circuit-level, remain unclear. <em>In vivo</em> pooled CRISPR screening with single‑cell readout (<em>in vivo</em> Perturb‑seq) has begun to fill this gap by mapping causal genes to defined cell states directly in animal tissues [11–14]. Here, we review recent developments and applications of <em>in vivo</em> Perturb-seq in the mouse brain and highlight the potential of utilizing human cellular systems to extend these approaches. Additionally, we discuss how <em>in vivo</em> Perturb-seq can couple genetic perturbation with physiological or environmental perturbations to better model psychiatric diseases with environmental triggers.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102424"},"PeriodicalIF":3.6,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145866434","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 : 2025-12-19DOI: 10.1016/j.gde.2025.102416
Elias T Friman, Wendy A Bickmore
Transcriptional regulation involves the binding of thousands of transcription factors (TFs) to hundreds of thousands of enhancers and promoters. How do the collective activities of these proteins and cis-regulatory elements achieve precise and dynamic gene regulation? At an individual enhancer, TFs can interact to affect each other’s binding and the recruitment of different co-factors, resulting in cooperative outputs. More recently, new types of cooperative behaviour between enhancers have been discovered. In this review, we consider whether some of the same principles could contribute to both TF and enhancer cooperativity, focusing specifically on positive cooperativity (or synergy) and the role of 3D chromatin organisation.
{"title":"Enhancer cooperativity in the folded genome","authors":"Elias T Friman, Wendy A Bickmore","doi":"10.1016/j.gde.2025.102416","DOIUrl":"10.1016/j.gde.2025.102416","url":null,"abstract":"<div><div>Transcriptional regulation involves the binding of thousands of transcription factors (TFs) to hundreds of thousands of enhancers and promoters. How do the collective activities of these proteins and cis-regulatory elements achieve precise and dynamic gene regulation? At an individual enhancer, TFs can interact to affect each other’s binding and the recruitment of different co-factors, resulting in cooperative outputs. More recently, new types of cooperative behaviour between enhancers have been discovered. In this review, we consider whether some of the same principles could contribute to both TF and enhancer cooperativity, focusing specifically on positive cooperativity (or synergy) and the role of 3D chromatin organisation.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102416"},"PeriodicalIF":3.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792128","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 : 2025-12-19DOI: 10.1016/j.gde.2025.102415
Erin N Gilbertson , Steven K Reilly
Understanding the genetic basis of phenotypic differences across species has been a longstanding goal of evolutionary biology since Darwin. While a recent proliferation of mammalian genomes has provided an unprecedented inventory of sequence differences between species, the vast majority are in noncoding loci, where it remains challenging to link genetic changes to function. Cis-regulatory elements (CREs) control gene expression via combinatorial, redundant, and context-dependent interactions that are both evolutionarily amenable to change but render their gene regulatory logic difficult to decipher. Recent advances in comparative genomics, functional profiling across species, and high-throughput perturbation assays have begun to catalog cross-species differences in gene expression and CRE function. In parallel, machine learning approaches trained on these data are beginning to predict cis-regulatory activity differences from DNA sequences alone. Here, we highlight recent advances in both experimental and computational strategies to study gene regulatory evolution.
{"title":"Integrating machine learning and functional genomics to study cross-species gene regulatory evolution","authors":"Erin N Gilbertson , Steven K Reilly","doi":"10.1016/j.gde.2025.102415","DOIUrl":"10.1016/j.gde.2025.102415","url":null,"abstract":"<div><div>Understanding the genetic basis of phenotypic differences across species has been a longstanding goal of evolutionary biology since Darwin. While a recent proliferation of mammalian genomes has provided an unprecedented inventory of sequence differences between species, the vast majority are in noncoding loci, where it remains challenging to link genetic changes to function. Cis-regulatory elements (CREs) control gene expression via combinatorial, redundant, and context-dependent interactions that are both evolutionarily amenable to change but render their gene regulatory logic difficult to decipher. Recent advances in comparative genomics, functional profiling across species, and high-throughput perturbation assays have begun to catalog cross-species differences in gene expression and CRE function. In parallel, machine learning approaches trained on these data are beginning to predict cis-regulatory activity differences from DNA sequences alone. Here, we highlight recent advances in both experimental and computational strategies to study gene regulatory evolution.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102415"},"PeriodicalIF":3.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771942","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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