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Results for “epigenome editing”

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At least 19 recordsLinked to original sources
PubMed2025

Activation of the imprinted Prader-Willi syndrome locus by CRISPR-based epigenome editing.

Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi syndrome (PWS) results from loss of paternally expressed imprinted genes on chromosome 15q11.2-q13.3, although the maternal allele is intact but epigenetically silenced. Using CRISPR repression and activation screens in human induced pluripotent stem cells (iPSCs), we identified genomic elements that control the expression of the PWS gene SNRPN from the paternal and maternal chromosomes. We showed that either targeted transcriptional activation or DNA demethylation can activate the silenced maternal SNRPN and downstream PWS transcripts. However, these two approaches function at unique regions, preferentially activating different transcript variants and involving distinct epigenetic reprogramming mechanisms. Remarkably, transient expression of the targeted demethylase leads to stable, long-term maternal SNRPN expression in PWS iPSCs. This work uncovers targeted epigenetic manipulations to reprogram a disease-associated imprinted locus and suggests possible therapeutic interventions.

Prader-Willi Syndrome↗
PubMed2017

Rapid and reversible epigenome editing by endogenous chromatin regulators.

Understanding the causal link between epigenetic marks and gene regulation remains a central question in chromatin biology. To edit the epigenome we developed the FIRE-Cas9 system for rapid and reversible recruitment of endogenous chromatin regulators to specific genomic loci. We enhanced the dCas9-MS2 anchor for genome targeting with Fkbp/Frb dimerizing fusion proteins to allow chemical-induced proximity of a desired chromatin regulator. We find that mSWI/SNF (BAF) complex recruitment is sufficient to oppose Polycomb within minutes, leading to activation of bivalent gene transcription in mouse embryonic stem cells. Furthermore, Hp1/Suv39h1 heterochromatin complex recruitment to active promoters deposits H3K9me3 domains, resulting in gene silencing that can be reversed upon washout of the chemical dimerizer. This inducible recruitment strategy provides precise kinetic information to model epigenetic memory and plasticity. It is broadly applicable to mechanistic studies of chromatin in mammalian cells and is particularly suited to the analysis of endogenous multi-subunit chromatin regulator complexes.Understanding the link between epigenetic marks and gene regulation requires the development of new tools to directly manipulate chromatin. Here the authors demonstrate a Cas9-based system to recruit chromatin remodelers to loci of interest, allowing rapid, reversible manipulation of epigenetic states.

CRISPR-Cas Systems↗
PubMed2025

Rescue of imprinted genes by epigenome editing in human cellular models of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genomic imprinting disorder caused by the loss of function of the paternal chromosome 15q11-13, resulting in a spectrum of symptoms associated with hypothalamic dysfunction. PWS patients lack the expression of paternally expressed genes (PEGs) in the 15q11-13 locus but possess an epigenetically silenced set of these genes in the maternal allele. Thus, activation of these silenced genes can serve as a therapeutic target for PWS. Here, we leverage CRISPR-based epigenome editing system to modulate the DNA methylation status of the PWS imprinting control region (PWS-ICR) in induced pluripotent stem cells (iPSCs) derived from PWS patients. Successful demethylation in the PWS-ICR restores the PEG expression from the maternal allele and reorganizes the methylation patterns in other PWS-associated imprinted regions beyond the PWS-ICR. Remarkably, these corrected epigenomic patterns and PEG expression are maintained following the differentiation of these cells into hypothalamic organoids. Finally, the single-cell transcriptomic analysis of epigenome-edited organoids demonstrates a partial restoration of the transcriptomic dysregulation observed in PWS. This study highlights the utility of epigenome editing technology as a therapeutic approach in addressing PWS and potentially other imprinting disorders.

Prader-Willi Syndrome↗
PubMed2026

In vivo epigenome editing reduces circulating lipids and attenuates atherosclerosis in mice.

Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with hypercholesterolemia serving as a critical driver of atherogenesis. Although current lipid-lowering therapies substantially improve circulating lipid profiles, strategies that provide more durable, safe, and efficient control of lipid metabolism are still needed. Epigenome editing offers a promising approach for long-lasting repression of disease-modifying genes without altering the underlying DNA sequence. Here, we develop CRISPRoff platforms delivered by adeno-associated virus or lipid nanoparticle to epigenetically silence hepatic Hmgcr or Pcsk9 in vivo. In both C57BL/6J wild-type and ApoE-/- mice, CRISPRoff mediates robust and durable repression of these targets, leading to marked reductions in circulating total cholesterol, low-density lipoprotein cholesterol, and triglycerides. In the ApoE-/- context, epigenetic silencing of Pcsk9 confers pronounced vascular protection, including decreased lipid accumulation in the liver and aortic root, reduced necrotic core formation, diminished macrophage infiltration, and enhanced plaque stability. Together, these results provide proof of principle that CRISPRoff-based epigenome editing enables stable repression of clinically relevant targets and ameliorates key features of atherosclerotic disease. This work lays the foundation for broader therapeutic applications of epigenetic modulation in cardiovascular disorders.

Animals↗
PubMed2025

CRISPRoff epigenome editing for programmable gene silencing in human cell lines and primary T cells.

The advent of CRISPR-based technologies has enabled the rapid advancement of programmable gene manipulation in cells, tissues, and whole organisms. An emerging platform for targeted gene perturbation is epigenetic editing, the direct editing of chemical modifications on DNA and histones that ultimately results in repression or activation of the targeted gene. In contrast to CRISPR nucleases, epigenetic editors modulate gene expression without inducing DNA breaks or altering the genomic sequence of host cells. Recently, we developed the CRISPRoff epigenetic editing technology that simultaneously establishes DNA methylation and repressive histone modifications at targeted gene promoters. Transient expression of CRISPRoff and the accompanying single guide RNAs in mammalian cells results in transcriptional repression of targeted genes that is memorized heritably by cells through cell division and differentiation. Here, we describe our protocol for the delivery of CRISPRoff through plasmid DNA transfection, as well as the delivery of CRISPRoff mRNA, into transformed human cell lines and primary immune cells. We also provide guidance on evaluating target gene silencing and highlight key considerations when utilizing CRISPRoff for gene perturbations. Our protocols are broadly applicable to other CRISPR-based epigenetic editing technologies, as programmable genome manipulation tools continue to evolve rapidly.

Humans↗
PubMed2026

The emerging impact of CRISPR and gene editing on global crop improvement.

The advent of CRISPR-based genome editing has revolutionized crop improvement, offering unprecedented precision and efficiency in modifying key agronomic traits. This review comprehensively examines the mechanisms, applications, and future potential of CRISPR technology in enhancing global crop production. CRISPR-Cas systems, originally identified as adaptive immune mechanisms in bacteria and archaea, have been repurposed for targeted genome editing in plants. The CRISPR-Cas9 system, in particular, has emerged as a powerful tool for introducing site-specific double-strand breaks, enabling precise genetic modifications. The three-stage process of adaptation, expression, and interference underlies the CRISPR mechanism, with guide RNAs directing Cas endonucleases to specific genomic loci. Advances in CRISPR technology have expanded its applications beyond gene knockouts, encompassing base editing, prime editing, and epigenome editing. These innovations have facilitated the development of crops with enhanced yield, stress tolerance, disease resistance, nutritional content, and post-harvest quality. However, challenges related to off-target effects, regulatory hurdles, ethical concerns, and public acceptance must be addressed to fully harness the potential of CRISPR in agriculture. Integration of CRISPR with other cutting-edge technologies, such as synthetic biology, artificial intelligence, and high-throughput phenotyping, holds immense promise for accelerating crop improvement efforts. As research continues to refine CRISPR tools and expand their applicability across diverse plant species, this transformative technology is poised to play a pivotal role in shaping a sustainable, resilient, and productive global food system for future generations.

Gene Editing↗
PubMed2025

HyperCas12a enables multiplexed CRISPRi screens.

Interactions between multiple genes or cis-regulatory elements (CREs) underlie a wide range of biological processes in both health and disease. High-throughput screens using dCas9 fused to epigenome editing domains have allowed researchers to assess the impact of activation or repression of both coding and non-coding genomic regions on a phenotype of interest, but assessment of genetic interactions between those elements has been limited to pairs. Here, we combine a hyper-efficient version of Lachnospiraceae bacterium dCas12a (dHyperLbCas12a) with RNA Polymerase II expression of long CRISPR RNA (crRNA) arrays to enable efficient highly-multiplexed epigenome editing. We demonstrate that this system is compatible with several activation and repression domains, including the P300 histone acetyltransferase domain and SIN3A interacting domain (SID). We further show that the system can be used in cultured primary immune cells and to drive differentiation of induced pluripotent stem cells. We also developed new approaches to use the dCas12a platform for simultaneous activation and repression from a single crRNA array via co-expression of multiple dCas12a orthologues. Lastly, we demonstrate that the dHyperLbCas12a effectors are highly effective for multiple modalities of high-throughput screens, namely proliferation screens and screens to dissect the independent and combinatorial contributions of CREs on gene expression. The tools and methods introduced here create new possibilities for highly multiplexed control of gene expression in a wide variety of biological systems.

Journal Article↗
PubMed2026

CRISPR-Cas technologies for precision genome editing in plants: advances, applications, and future perspectives.

Developing climate-smart crops with enhanced crop productivity, nutritional quality, resistance to biological and environmental stressors is vital for global food security. While hybrid breeding forms the cornerstone of modern crop improvement, conventional breeding approaches are limited by genetic barriers and prolonged breeding cycles. CRISPR-Cas based genome editing has revolutionized plant biology by allowing precise, efficient, and multiplex genetic modifications. This review provides a comprehensive synthesis of a recent advances in CRISPR-Cas technologies and their strategic applications in crop genetics and hybrid breeding. We summarize major genome-editing strategies, including gene knock-out, base editing (BE), knock-in, gene replacement, epigenome editing, and transcriptional regulation. Furthermore, we contrast stable, transient, and DNA-free delivery systems, highlighting ribonucleoprotein (RNP)-mediated delivery for minimizing off-target effects and avoiding transgene integration. We showcase how these technologies accelerate hybrid breeding by engineering male sterility systems, fixing heterosis, and generating high-throughput mutant libraries for trait discovery. Finally, we synthesize major bottlenecks in tissue culture-independent transformation and delivery systems, while outlining how emerging paradigms like de novo domestication and synthetic biology will shape the future of climate-resilient agriculture.

CRISPR/Cas↗
PubMed2025

Self-organization of mouse embryonic stem cells into reproducible pre-gastrulation embryo models via CRISPRa programming.

Embryonic stem cells (ESCs) can self-organize into structures with spatial and molecular similarities to natural embryos. During development, embryonic and extraembryonic cells differentiate through activation of endogenous regulatory elements while co-developing via cell-cell interactions. However, engineering regulatory elements to self-organize ESCs into embryo models remains underexplored. Here, we demonstrate that CRISPR activation (CRISPRa) of two regulatory elements near Gata6 and Cdx2 generates embryonic patterns resembling pre-gastrulation mouse embryos. Live single-cell imaging revealed that self-patterning occurs through orchestrated collective movement driven by cell-intrinsic fate induction. In 3D, CRISPRa-programmed embryo models (CPEMs) exhibit morphological and transcriptomic similarity to pre-gastrulation mouse embryos. CPEMs allow versatile perturbations, including dual Cdx2-Elf5 activation to enhance trophoblast differentiation and lineage-specific activation of laminin and matrix metalloproteinases, uncovering their roles in basement membrane remodeling and embryo model morphology. Our findings demonstrate that minimal intrinsic epigenome editing can self-organize ESCs into programmable pre-gastrulation embryo models with robust lineage-specific perturbation capabilities.

Animals↗
PubMed2023

CasKAS: direct profiling of genome-wide dCas9 and Cas9 specificity using ssDNA mapping.

Detecting and mitigating off-target activity is critical to the practical application of CRISPR-mediated genome and epigenome editing. While numerous methods have been developed to map Cas9 binding specificity genome-wide, they are generally time-consuming and/or expensive, and not applicable to catalytically dead CRISPR enzymes. We have developed CasKAS, a rapid, inexpensive, and facile assay for identifying off-target CRISPR enzyme binding and cleavage by chemically mapping the unwound single-stranded DNA structures formed upon binding of a sgRNA-loaded Cas9 protein. We demonstrate this method in both in vitro and in vivo contexts.

CRISPR-Cas Systems↗
PubMed2026

Epigenetic and Transcriptional Regulatory Networks Underlying Psoriasis Pathogenesis.

Psoriasis is a chronic, immune-mediated dermatologic disorder characterized by the hyperproliferation of keratinocytes and dysregulated immune signaling. Although genome-wide association studies have identified susceptibility loci, the multifactorial nature of the disease underlines the importance of nongenetic regulatory mechanisms. Among these epigenetic modifications are those that critically link genetic predisposition with environmental stimuli. This review offers an in-depth overview of the current insights into the role of epigenetic regulation in the pathophysiology of psoriasis. Key mechanisms, including aberrant DNA methylation, histone post-translational modifications (eg, H3K27ac, H3K4me3), and dysregulated noncoding RNAs, are discussed in the context of inflammatory signaling and immune cell function. This review also explores how environmental factors such as UV radiation and air pollution induce the epigenetic reprogramming that perpetuates the proinflammatory state. Furthermore, it highlights the translational potential of targeting epigenetic regulators and epigenome-editing technologies, including clustered regularly interspaced short palindromic repeats (CRISPR) fusion systems, as precision therapeutic strategies. In parallel, advances in single-cell epigenomics, spatial transcriptomics, and the profiling of circulating biomarkers offer novel diagnostic tools. Despite advances, challenges persist, including the limited predictive value of preclinical models and variable epigenetic profiles. Positioning epigenetics as the bridge between genetic risk, environmental triggers, and therapeutic advances, this review presents a framework for precision medicine in psoriasis.

Humans↗
PubMed2026

Inheritance of the epigenetic signature and reduced intermuscular bone phenotype acquired via DNA methylation editing of the runx2 b promoter in zebrafish.

The presence of intermuscular bones (IBs) can directly affect the economic value of aquaculture fish. Although genome editing can create IB-free fish by knocking out key IB-related genes, such as runx2b, the associated DNA sequence alterations raise food safety and health concerns, limiting its breeding applications. In this study, we used CRISPR/dCas9-mediated epigenome-editing technology targeting the runx2 b promoter in zebrafish to alter DNA methylation patterns without changing the DNA sequence. Our results showed that higher runx2 b promoter methylation patterns significantly inhibited eGFP mRNA expression levels in the recombinant plasmid. Using the CRISPR/dCas9-Dnmt7 system to enhance methylation of the zebrafish runx2b promoter, we observed a significant decrease in runx2 b mRNA expression levels in the F0 generation. The IBs in the 11 th-16 th muscle segments of the adult F0 fish were significantly shorter compared with the controls. Inbreeding of fish was used to produce F1 and F2 offspring that retained these high promoter methylation levels, along with persistent runx2b expression suppression and IB development inhibition. Transcriptome sequencing analysis suggested that increasing runx2 b promoter methylation levels may synergistically induce additional epigenetic modifications, potentially affecting the PPAR signaling pathway and FoxO transcription factor regulation, which appears to inhibit osteoblast proliferation and differentiation. Overall, this study demonstrates an innovative application of epigenetic editing technology for aquaculture breeding. By precisely regulating the expression patterns of key genes for economically important traits while preserving genomic DNA integrity, this approach provides a theoretical foundation and technical support for improving fish economic traits.

Animals↗
PubMed2024

Induced proximity labeling and editing for epigenetic research.

Epigenetic regulation plays a pivotal role in various biological and disease processes. Two key lines of investigation have been pursued that aim to unravel endogenous epigenetic events at particular genes (probing) and artificially manipulate the epigenetic landscape (editing). The concept of induced proximity has inspired the development of powerful tools for epigenetic research. Induced proximity strategies involve bringing molecular effectors into spatial proximity with specific genomic regions to achieve the probing or manipulation of local epigenetic environments with increased proximity. In this review, we detail the development of induced proximity methods and applications in shedding light on the intricacies of epigenetic regulation.

Epigenesis, Genetic↗
PubMed2025

Gene regulation technologies for gene and cell therapy.

Gene therapy stands at the forefront of medical innovation, offering unique potential to treat the underlying causes of genetic disorders and broadly enable regenerative medicine. However, unregulated production of therapeutic genes can lead to decreased clinical utility due to various complications. Thus, many technologies for controlled gene expression are under development, including regulated transgenes, modulation of endogenous genes to leverage native biological regulation, mapping and repurposing of transcriptional regulatory networks, and engineered systems that dynamically react to cell state changes. Transformative therapies enabled by advances in tissue-specific promoters, inducible systems, and targeted delivery have already entered clinical testing and demonstrated significantly improved specificity and efficacy. This review highlights next-generation technologies under development to expand the reach of gene therapies by enabling precise modulation of gene expression. These technologies, including epigenome editing, antisense oligonucleotides, RNA editing, transcription factor-mediated reprogramming, and synthetic genetic circuits, have the potential to provide powerful control over cellular functions. Despite these remarkable achievements, challenges remain in optimizing delivery, minimizing off-target effects, and addressing regulatory hurdles. However, the ongoing integration of biological insights with engineering innovations promises to expand the potential for gene therapy, offering hope for treating not only rare genetic disorders but also complex multifactorial diseases.

Humans↗
PubMed2025

A First-in-Class Chemical-Induced Proximity System Achieves Dose-Dependent Control of Tumor Protein P53 Gene Activation in Preclinical Models of Gastric Cancer.

The tumor protein P53 (TP53) gene has long been studied in cancer research with genomic and epigenetic aberrations playing a driving role in cancer pathology, yet even after decades of work, only a few methods have been developed to specifically target TP53 therapeutically. Some cancers are driven by loss-of-function TP53 mutations, while others have wild-type TP53 in a transcriptionally repressed state; the latter is exploitable by advances in epigenome editing. In our previous work, we demonstrated that deactivated CRISPR/Cas9 systems (dCas9), combined with an FK-506-binding protein (FKBP) recruitment protein tag and chemical epigenetic modifier (CEM) small molecules, can elicit gene-specific changes in expression in a dose-dependent manner. Here, we describe the development, application, and characterization of the dCas9-FKBP-CEM technology to increase TP53 expression. We demonstrate that catalyzing increased TP53 expression via dCas9-FKBP-CEM87 induced apoptosis, cell cycle arrest, and tumor growth inhibition in a dose-dependent manner in preclinical models of gastric cancer.

CRISPR↗
PubMed2026

Epigenetics and childhood obesity: DNA methylation coordinates environment and gene regulation.

Childhood obesity is a complex disorder which results from the combined contribution of genetics, the environment, and development, which is programmed and coordinated by epigenetic mechanisms. Of them, DNA methylation has emerged as an important molecular interface between environmental inputs and changes in gene expression. In this review, we provide an overview of the role of DNA methylation in childhood obesity during the key developmental stages, from prenatal life and childhood to adolescence. We also highlight the available evidence from candidate genes and genome-wide association studies implicating critical loci involved in energy homeostasis and adipogenesis, where DNA methylation is altered. Further, we also provide an overview of how maternal obesity, nutritional status, and bariatric surgery shape offspring's methylation profiles and contribute to the increased risk of programming obesity across generations. Although aberrant methylation patterns are consistently associated with altered metabolic phenotypes, disentangling causality remains a significant challenge. Herein, we highlight emerging approaches, such as rigorous longitudinal cohorts, epigenetic Mendelian randomization, and CRISPR-based epigenome editing, that are beginning to provide the analytical clarity needed to move beyond association. Finally, we examine the potential of DNA methylation signatures to inform early risk stratification and prevention possibilities. Although yet to be clinically validated, whole-genome methylation profiling is increasingly integrated with systems biology and multi-omics frameworks, making the identification of robust, clinically actionable markers more promising. A more precise understanding of how epigenetic processes shape susceptibility to childhood obesity could ultimately support strategies capable of altering lifelong metabolic trajectories.

Humans↗
PubMed2026

Light-activated CRISPR/dCas9 nanomedicine for programmable control of renal fibrosis.

Renal fibrosis is the final common pathway of progressive chronic kidney disease and is maintained by spatially heterogeneous interactions among injured epithelial cells, activated fibroblasts, immune cells, extracellular matrix remodeling, metabolic stress, and persistent profibrotic transcriptional programs. Current therapies slow renal functional decline but do not directly control the regulatory circuits that stabilize maladaptive repair. Photoresponsive renal nanomedicine offers a potential strategy to add external control to anti-fibrotic intervention by combining kidney-directed delivery with light-gated release or activation of molecular payloads. This review examines the emerging interface between photoresponsive nanomaterials and CRISPR/dCas9-based gene regulation for renal fibrosis, with emphasis on upconversion nanoparticles, photoresponsive polymers, ROS- and pH-responsive matrices, optogenetic switches, and renal-compartment-directed carrier design. We argue that the most defensible therapeutic objective is not permanent genome editing or autonomous organ regeneration, but spatially confined, temporally limited, and reversible regulation of validated fibrotic or protective gene programs using CRISPRa, CRISPRi, or dCas9-based epigenome editors. The review therefore evaluates material requirements, optical-dosimetry constraints, payload architecture, renal biodistribution, target-selection logic, safety risks, and preclinical validation criteria. By defining the engineering and biological conditions required for controlled anti-fibrotic regulation, this framework positions photoresponsive renal nanomedicine as a translationally testable route toward localized modulation of fibrotic cell states rather than an overextended claim of kidney regeneration.

Anti-fibrotic gene regulation↗
PubMed2025

Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates.

Epigenetic editing is a promising strategy for modifying gene expression while avoiding the permanent alterations and potential genotoxicity of genome-editing technologies. Here we designed optimized epigenetic regulators (EpiRegs) by testing combinations of transcription activator-like effector (TALE)-based and catalytically deactivated Cas9 (dCas9)-based epigenetic modification effectors and fusion protein structures. TALE-based EpiReg (EpiReg-T) achieved a final efficiency of 98% in mice, surpassing the initial dCas9-based efficiency of 64%. We demonstrated the approach in macaques by introducing DNA methylation and histone modifications to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, thereby lowering low-density lipoprotein cholesterol levels. A single dose of EpiReg-T delivered with lipid nanoparticles achieved efficient (>90%) and long-lasting (343 days) silencing of PCSK9 in the liver. Integrative multiomic analyses revealed minimal off-target effects in EpiReg-T-treated monkeys, mice and human-derived cells. EpiReg can be redirected to other genes by reengineering the DNA-binding domain. Our findings represent a step toward the clinical application of epigenetic editing for the treatment of human diseases.

Animals↗