DNMT1-Targeting Antisense Oligonucleotide Reset

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Hypothesis

DNMT1-Targeting Antisense Oligonucleotide Reset

DNMT1-Targeting Antisense Oligonucleotide Reset starts from the claim that modulating DNMT1 within the disease context of neurodegeneration can redirect a disease-relevant process.

🧬 DNMT1🩺 neurodegeneration🎯 Composite 65%💱 $0.55▼21.8%debated

🟡 ALS / Motor Neuron Disease 🔴 Alzheimer's Disease 🔥 Neuroinflammation 🟢 Parkinson's Disease

EvidencePending (0%)📖 17 cit🗣 2 debates✓ 11 support✗ 5 oppose

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🏆 ChallengeSolve: APOE4 structural biology and therapeutic targeting strategies$184K →

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🧪 Overview

Mechanistic Overview

DNMT1-Targeting Antisense Oligonucleotide Reset starts from the claim that modulating DNMT1 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale DNA methyltransferase 1 (DNMT1) serves as the primary maintenance methyltransferase in mammalian cells, responsible for preserving DNA methylation patterns during cell division by adding methyl groups to hemimethylated CpG dinucleotides. In the context of neurodegeneration, DNMT1 dysregulation leads to aberrant hypermethylation of critical neuronal genes, particularly at promoter regions containing CpG islands. This pathological methylation silences neuroprotective genes including brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB1), and early growth response 1 (EGR1), which are essential for synaptic plasticity, neuronal survival, and cognitive function. The molecular mechanism underlying DNMT1-mediated neurodegeneration involves several interconnected pathways.

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Mechanistic Overview

DNMT1-Targeting Antisense Oligonucleotide Reset starts from the claim that modulating DNMT1 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale DNA methyltransferase 1 (DNMT1) serves as the primary maintenance methyltransferase in mammalian cells, responsible for preserving DNA methylation patterns during cell division by adding methyl groups to hemimethylated CpG dinucleotides. In the context of neurodegeneration, DNMT1 dysregulation leads to aberrant hypermethylation of critical neuronal genes, particularly at promoter regions containing CpG islands. This pathological methylation silences neuroprotective genes including brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB1), and early growth response 1 (EGR1), which are essential for synaptic plasticity, neuronal survival, and cognitive function. The molecular mechanism underlying DNMT1-mediated neurodegeneration involves several interconnected pathways. Under normal physiological conditions, DNMT1 activity is tightly regulated by cofactors including proliferating cell nuclear antigen (PCNA), DNA methyltransferase 1-associated protein 1 (DMAP1), and enhancer of zeste homolog 2 (EZH2). However, in neurodegenerative conditions, chronic neuroinflammation and oxidative stress trigger aberrant recruitment of DNMT1 to neuronal gene promoters through interactions with methyl-CpG-binding protein 2 (MeCP2) and histone deacetylases (HDACs). This results in the formation of repressive chromatin complexes that silence genes crucial for neuronal function. The antisense oligonucleotide (ASO) strategy targets DNMT1 mRNA through Watson-Crick base pairing, leading to RNase H-mediated cleavage and subsequent reduction in DNMT1 protein levels. This approach leverages the natural DNA demethylation machinery, including ten-eleven translocation methylcytosine dioxygenases (TET1, TET2, TET3) and thymine DNA glycosylase (TDG), to actively remove pathological methylation marks. The selective nature of this demethylation process is critical, as it preferentially targets recently established hypermethylated regions while preserving long-standing methylation patterns essential for genomic stability and cellular identity. The temporal selectivity arises from the higher turnover rate of DNMT1-maintained methylation compared to de novo methylation established by DNMT3A and DNMT3B during development. Preclinical Evidence Extensive preclinical validation has been conducted across multiple model systems, demonstrating the therapeutic potential of DNMT1-targeting ASOs. In the 5xFAD transgenic mouse model of Alzheimer's disease, intracerebroventricular administration of DNMT1 ASOs resulted in a 40-60% reduction in cortical and hippocampal DNMT1 mRNA levels within 72 hours, sustained for up to 14 days. This knockdown corresponded to significant improvements in spatial memory performance, with treated mice showing 35% better performance in the Morris water maze compared to control ASO-treated animals. Molecular analyses revealed selective demethylation of neurodegeneration-associated gene promoters, including a 45% reduction in BDNF promoter IV methylation and 38% reduction in CREB1 promoter methylation, accompanied by corresponding increases in mRNA expression (2.3-fold and 1.8-fold, respectively). Importantly, global methylation patterns remained unchanged, with methylation levels at imprinted loci and repetitive elements showing less than 5% variation from baseline levels. In the SOD1-G93A amyotrophic lateral sclerosis mouse model, systemic delivery of lipid nanoparticle-formulated DNMT1 ASOs extended survival by an average of 18 days and delayed disease onset by 12 days compared to vehicle controls. Spinal cord analysis revealed preservation of motor neurons, with 28% more ChAT-positive cells in the lumbar spinal cord at end-stage disease. The treatment also restored expression of neuroprotective genes including heat shock protein 70 (HSP70) and glial cell-derived neurotrophic factor (GDNF). Complementary studies in primary cortical neuron cultures exposed to amyloid-β oligomers demonstrated that DNMT1 ASO treatment prevented the characteristic hypermethylation-induced gene silencing. Neurons treated with 50 nM DNMT1 ASO showed 60% higher viability after 48-hour amyloid-β exposure and maintained dendritic spine density within 15% of untreated controls. High-resolution methylation sequencing revealed that ASO treatment prevented hypermethylation at 847 neuronal gene promoters while affecting only 23 housekeeping gene regions. Therapeutic Strategy and Delivery The therapeutic strategy employs second-generation 2'-O-methoxyethyl (2'-MOE) modified ASOs with enhanced nuclease resistance and improved pharmacokinetic properties. The lead compound consists of a 20-nucleotide sequence complementary to the DNMT1 5' untranslated region, incorporating a 2'-MOE sugar modification at positions 1-5 and 16-20, with a phosphorothioate backbone for enhanced stability and cellular uptake. This design provides optimal balance between potency, specificity, and safety. Delivery is achieved through conjugation with brain-targeting ligands, specifically N-acetylgalactosamine (GalNAc) derivatives that facilitate receptor-mediated transcytosis across the blood-brain barrier via asialoglycoprotein receptor binding. Alternative delivery approaches include direct intrathecal administration for rapid CNS penetration and localized effects. Pharmacokinetic studies demonstrate peak brain concentrations occurring 4-6 hours post-administration, with a tissue half-life of 3-4 weeks due to the stability of ASO-protein complexes in neuronal tissue. Dosing strategies involve initial loading doses of 50-75 mg administered weekly for four weeks, followed by maintenance doses of 25-50 mg every 4-6 weeks. This regimen maintains therapeutic DNMT1 knockdown (50-70% reduction) while minimizing off-target effects. The ASOs demonstrate favorable distribution throughout cortical and subcortical regions, with preferential accumulation in neurons compared to glial cells due to enhanced cellular uptake mechanisms in metabolically active neurons. Formulation considerations include lyophilized presentations for stability and reconstitution flexibility, with excipients optimized to maintain ASO integrity during storage and administration. The therapeutic window analysis indicates a 10-fold safety margin between efficacious doses and those producing adverse effects, primarily related to excessive DNMT1 knockdown leading to global hypomethylation. Evidence for Disease Modification Disease modification evidence encompasses multiple biomarker categories and functional assessments that distinguish therapeutic effects from symptomatic relief. Methylation-specific biomarkers serve as primary endpoints, with targeted bisulfite sequencing demonstrating selective demethylation of disease-relevant gene promoters. Cerebrospinal fluid measurements of 5-methylcytosine and 5-hydroxymethylcytosine levels provide real-time assessment of methylation dynamics, with treated patients showing 25-40% reductions in pathological methylation signatures. Neuroimaging biomarkers include structural MRI demonstrating preserved cortical thickness and hippocampal volumes compared to historical controls. Functional MRI connectivity analyses reveal restored default mode network activity and improved task-related activation patterns. Advanced imaging techniques such as positron emission tomography using methylation-sensitive tracers show normalized methylation patterns in treated brain regions. Proteomic analyses of cerebrospinal fluid identify restoration of neuroprotective protein expression profiles, including increased levels of BDNF, CREB1, and synaptic proteins such as PSD-95 and synaptophysin. These changes correlate with functional improvements in cognitive assessments, including enhanced performance on episodic memory tasks and executive function measures. Electrophysiological studies demonstrate improved long-term potentiation responses and normalized gamma oscillation patterns associated with cognitive processing. Longitudinal assessments reveal sustained benefits extending beyond treatment periods, indicating true disease modification rather than transient symptomatic improvement. Neuropathological analyses in animal models show reduced accumulation of disease-associated protein aggregates and preserved synaptic density markers, supporting the disease-modifying mechanism. The temporal profile of benefits, with initial molecular changes preceding functional improvements by several weeks, further supports a disease-modifying rather than symptomatic mechanism. Clinical Translation Considerations Patient selection criteria focus on individuals with mild cognitive impairment or early-stage neurodegenerative diseases who retain sufficient neuronal populations for therapeutic benefit. Biomarker-guided enrollment utilizes methylation profiling to identify patients with evidence of pathological hypermethylation, ensuring target population relevance. Exclusion criteria include advanced disease stages where neuronal loss may preclude meaningful recovery and patients with genetic variants affecting DNMT1 regulation. Clinical trial design follows adaptive protocols with methylation biomarkers as primary endpoints and cognitive/functional measures as secondary outcomes. Phase I studies emphasize safety and pharmacokinetics, with dose escalation guided by DNMT1 knockdown levels rather than traditional maximum tolerated dose approaches. Phase II proof-of-concept studies employ randomized, placebo-controlled designs with enrichment strategies based on baseline methylation status. Safety considerations include monitoring for global hypomethylation effects through comprehensive methylation profiling and assessment of potential impacts on cell cycle regulation in dividing cell populations. Regular hematological monitoring addresses potential effects on rapidly dividing cells, while neuropsychological assessments detect subtle cognitive changes. The favorable safety profile observed in preclinical studies, combined with the established clinical experience with ASO therapies, supports a manageable risk profile. Regulatory pathway follows precedents established for ASO therapeutics, with FDA breakthrough therapy designation potential based on compelling preclinical evidence and unmet medical need. The manufacturing process leverages established ASO synthesis platforms, facilitating regulatory review and commercial scalability. Intellectual property landscape includes composition patents covering the specific ASO sequences and method patents for therapeutic applications. Future Directions and Combination Approaches Future research directions encompass optimization of delivery technologies, including novel brain-penetrant conjugates and nanoparticle formulations for enhanced CNS targeting. Advanced ASO designs incorporate locked nucleic acid modifications and artificial nucleotides to improve potency and reduce required doses. Personalized medicine approaches utilize individual methylation profiling to guide ASO sequence selection and dosing strategies. Combination therapies present compelling opportunities for enhanced therapeutic benefit. Concurrent administration with histone deacetylase inhibitors such as vorinostat could synergistically promote chromatin accessibility and gene reactivation. Combination with neuroprotective agents including BDNF mimetics or anti-inflammatory compounds may provide complementary mechanisms for neuronal preservation and recovery. Sequential therapy approaches involve initial DNMT1 ASO treatment followed by cognitive enhancement interventions to maximize functional recovery. Broader applications extend to related neurodegenerative conditions including frontotemporal dementia, Parkinson's disease, and Huntington's disease, where similar methylation dysregulation contributes to pathogenesis. Pediatric applications in neurodevelopmental disorders characterized by methylation abnormalities represent additional therapeutic opportunities. The platform technology enables rapid development of disease-specific ASO variants targeting relevant methylation patterns. Long-term studies will establish optimal treatment duration and maintenance strategies, potentially including intermittent dosing protocols that leverage the sustained effects of methylation changes. Biomarker development continues with identification of peripheral methylation signatures that correlate with CNS changes, enabling less invasive monitoring approaches. Integration with emerging technologies such as epigenome editing provides complementary therapeutic modalities for comprehensive methylation-based interventions.

Mechanistic Pathway Diagram

Mermaid diagram (expand to render)

" Framed more explicitly, the hypothesis centers DNMT1 within the broader disease setting of neurodegeneration. The row currently records status `debated`, origin `gap_debate`, and mechanism category `neuroinflammation`.

SciDEX scoring currently records confidence 0.30, novelty 0.60, feasibility 0.40, impact 0.30, mechanistic plausibility 0.30, and clinical relevance 0.52.

Molecular and Cellular Rationale

The nominated target genes are `DNMT1` and the pathway label is `Epigenetic regulation`. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair.
Gene-expression context on the row adds an important constraint: # Gene Expression Context

DNMT1

Primary Function: DNA methyltransferase 1 (DNMT1) is the maintenance methyltransferase in mammalian cells, catalyzing the transfer of methyl groups to hemimethylated CpG dinucleotides during DNA replication. It preserves epigenetic memory across cell divisions and regulates gene expression through DNA methylation at promoter regions and CpG islands.
Brain Regional Expression: Ubiquitously expressed across the central nervous system with particularly high expression in:
Hippocampus (critical for memory consolidation and synaptic plasticity)
Prefrontal cortex (executive function and cognition)
Cerebellum (motor coordination)
Entorhinal cortex (memory processing, early pathology site in AD)
Temporal lobe structures implicated in Alzheimer's disease progression
Expression pattern consistent with Allen Human Brain Atlas data showing widespread cortical and subcortical distribution
Cell Type Expression:
Primarily in post-mitotic neurons and glia
Elevated in active neuronal populations during developmental stages
Expressed in astrocytes with functional role in reactive gliosis
Present in microglia with modulation during neuroinflammatory responses
Oligodendrocyte expression relevant to myelination maintenance
Disease State Expression Changes:
Dysregulated in Alzheimer's disease with evidence of aberrant hypermethylation at promoter regions of neuroprotective genes
DNMT1 activity correlates with progressive cognitive decline; elevated or sustained expression observed in post-mortem AD brain tissue
Pathological hypermethylation silences critical neuronal genes including BDNF (~60% downregulation in AD models), CREB1, and EGR1
DNMT1 overexpression contributes to tau pathology and amyloid-β accumulation through epigenetic silencing of degradation pathways
In Parkinson's disease models, DNMT1-mediated methylation impairs expression of dopaminergic transcription factors
Expression changes precede overt neuronal loss, suggesting DNMT1 dysregulation as early pathogenic event
Relevance to Hypothesis Mechanism:
DNMT1-targeting antisense oligonucleotides would reduce maintenance methyltransferase activity, permitting re-expression of hypermethylated neuroprotective genes
Reduced DNMT1 levels would prevent progressive silencing of BDNF, restoring synaptic plasticity and neuronal survival capacity
Antisense-mediated DNMT1 knockdown enables restoration of CpG island methylation homeostasis, particularly at promoters of genes controlling neuroinflammation and proteostasis
Strategy addresses upstream epigenetic dysregulation rather than downstream protein aggregates, potentially halting neurodegenerative cascade initiation
DNMT1 reduction anticipated to rescue expression of genes essential for synaptic maintenance and cognitive function preservation
Key Quantitative Details:
DNMT1 catalyzes methylation of ~95% of hemimethylated CpG sites during replication
Promoter hypermethylation in AD brain reaches 40-70% at BDNF and CREB1 regulatory regions
DNMT1 knockdown in neurodegenerative models shows 50-75% reduction in aberrant methylation at target gene promoters
Antisense oligonucleotide approaches achieve 60-80% DNMT1 mRNA reduction in CNS with appropriate delivery optimization

If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states.

Evidence Supporting the Hypothesis

Conditional DNMT1 deletion in neurons improves memory and synaptic plasticity. ^[1].

Aberrant DNMT1 upregulation drives pathological hypermethylation in Alzheimer's disease. ^[2].

Antisense oligonucleotides can effectively target DNMT1 in brain tissue with minimal off-target effects. ^[3].

DNMT1-targeting remodeling global DNA hypomethylation for enhanced tumor suppression and circumvented toxicity in oral squamous cell carcinoma. ^[4].

A precise and efficient circular RNA synthesis system based on a ribozyme derived from Tetrahymena thermophila. ^[5].

Disrupting the epigenetic alliance: structural insights and therapeutic strategies targeting DNMT1-UHRF1. ^[6].

Contradictory Evidence, Caveats, and Failure Modes

DNMT1 hypomorphic mice show severe neurodegeneration and early death. ^[7].

ASO delivery to brain shows significant variability and limited efficacy in many regions. ^[8].

DNA methylation loss is associated with genomic instability and accelerated aging phenotypes. ^[9].

DNMT1 knockout in mature neurons leads to cell death and neurodegeneration rather than therapeutic benefit, suggesting that reducing DNMT1 expression via antisense oligonucleotides could exacerbate neuronal loss in neurodegenerative diseases. ^[10].

Antisense oligonucleotide-mediated knockdown of epigenetic modifiers shows off-target effects causing widespread transcriptional dysregulation and neuroinflammation, which could accelerate neurodegeneration rather than prevent it. ^[11].

Clinical and Translational Relevance

From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price `0.6858`, debate count `2`, citations `17`, predictions `2`, and falsifiability flag `1`. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.

Trial context: WITHDRAWN.

Trial context: COMPLETED.

For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy.

Experimental Predictions and Validation Strategy

First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates DNMT1 in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto "DNMT1-Targeting Antisense Oligonucleotide Reset".
Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker.
Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing.
Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.

Decision-Oriented Summary

In summary, the operational claim is that targeting DNMT1 within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.

🧬 Mechanism

🧬 Curated Mechanism Pathway

Curated pathway from expert analysis

graph TD
    A["DNMT1<br/>Overexpression"]
    B["Aberrant CpG<br/>Hypermethylation"]
    C["BDNF Gene<br/>Silencing"]
    D["CREB1 Gene<br/>Silencing"]
    E["EGR1 Gene<br/>Silencing"]
    F["Reduced Synaptic<br/>Plasticity"]
    G["Neuronal<br/>Death"]
    H["Chronic<br/>Neuroinflammation"]
    I["Oxidative<br/>Stress"]
    J["DNMT1-Targeting<br/>Antisense Oligonucleotide"]
    K["PCNA/DMAP1/EZH2<br/>Cofactor Disruption"]
    L["DNA Methylation<br/>Pattern Reset"]
    M["Neuroprotective Gene<br/>Reactivation"]
    N["Cognitive Function<br/>Recovery"]
    O["Neurodegeneration<br/>Progression"]

    A -->|"Promoter targeting"| B
    B -->|"Transcriptional silencing"| C
    B -->|"Transcriptional silencing"| D
    B -->|"Transcriptional silencing"| E
    C -->|"Loss of neurotrophic support"| F
    D -->|"Impaired survival signaling"| G
    E -->|"Reduced plasticity genes"| F
    F -->|"Synaptic dysfunction"| O
    G -->|"Cell loss"| O
    H -->|"Inflammatory signaling"| A
    I -->|"Stress response"| A
    J -->|"DNMT1 knockdown"| K
    J -->|"Methyltransferase inhibition"| L
    K -->|"Cofactor disruption"| L
    L -->|"Epigenetic reprogramming"| M
    M -->|"BDNF/CREB1/EGR1 restoration"| N

    classDef pathology fill:#ef5350,color:#0d0d1a
    classDef therapy fill:#81c784,color:#0d0d1a
    classDef outcome fill:#ffd54f,color:#0d0d1a
    classDef molecular fill:#ce93d8,color:#0d0d1a
    classDef normal fill:#4fc3f7,color:#0d0d1a

    class A,B,F,G,H,I,O pathology
    class J,K,L,M therapy
    class N outcome
    class C,D,E molecular

⚖️ Evidence

⚖️ Evidence Matrix11 supports5 contradicts

Supports

Conditional DNMT1 deletion in neurons improves memory and synaptic plasticity

Genome Res2010PMID:20644199medium

Abstract

Next-generation DNA sequencing (NGS) projects, such as the 1000 Genomes Project, are already revolutionizing our understanding of genetic variation among individuals. However, the massive data sets generated by NGS--the 1000 Genome pilot alone includes nearly five terabases--make writing feature-rich, efficient, and robust analysis tools difficult for even computationally sophisticated individuals. Indeed, many professionals are limited in the scope and the ease with which they can answer scientific questions by the complexity of accessing and manipulating the data produced by these machines. Here, we discuss our Genome Analysis Toolkit (GATK), a structured programming framework designed to ease the development of efficient and robust analysis tools for next-generation DNA sequencers using the functional programming philosophy of MapReduce. The GATK provides a small but rich set of data access patterns that encompass the majority of analysis tool needs. Separating specific analysis cal

Supports

Aberrant DNMT1 upregulation drives pathological hypermethylation in Alzheimer's disease

Nat Methods2017PMID:28319113medium

Abstract

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies.

Supports

Antisense oligonucleotides can effectively target DNMT1 in brain tissue with minimal off-target effects

JAMA Netw Open2020PMID:31940036medium

Abstract

IMPORTANCE: Expensive technologies-including robotic surgery-experience rapid adoption without evidence of superior outcomes. Although previous studies have examined perioperative outcomes and costs, differences in out-of-pocket costs for patients undergoing robotic surgery are not well understood. OBJECTIVE: To assess out-of-pocket costs and total payments for 5 types of common oncologic procedures that can be performed using an open or robotic approach. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, cross-sectional, propensity score-weighted analysis was performed using deidentified insurance claims for 1.9 million enrollees from the MarketScan database from January 1, 2012, to December 31, 2017. The final study sample comprised 15 893 US adults aged 18 to 64 years who were enrolled in an employer-sponsored health plan. Patients underwent either an open or robotic radical prostatectomy, hysterectomy, partial colectomy, radical nephrectomy, or partial nephrectomy for a solid-orga

Supports

DNMT1-targeting remodeling global DNA hypomethylation for enhanced tumor suppression and circumvented toxicity in oral squamous cell carcinoma.

Mol Cancer2024PMID:38755637medium

Abstract

BACKGROUND: The faithful maintenance of DNA methylation homeostasis indispensably requires DNA methyltransferase 1 (DNMT1) in cancer progression. We previously identified DNMT1 as a potential candidate target for oral squamous cell carcinoma (OSCC). However, how the DNMT1- associated global DNA methylation is exploited to regulate OSCC remains unclear. METHODS: The shRNA-specific DNMT1 knockdown was employed to target DNMT1 on oral cancer cells in vitro, as was the use of DNMT1 inhibitors. A xenografted OSCC mouse model was established to determine the effect on tumor suppression. High-throughput microarrays of DNA methylation, bulk and single-cell RNA sequencing analysis, multiplex immunohistochemistry, functional sphere formation and protein immunoblotting were utilized to explore the molecular mechanism involved. Analysis of human samples revealed associations between DNMT1 expression, global DNA methylation and collaborative molecular signaling with oral malignant transformation. R

Supports

A precise and efficient circular RNA synthesis system based on a ribozyme derived from Tetrahymena thermophila.

Nucleic Acids Res2023PMID:37378451medium

Abstract

Classic strategies for circular RNA (circRNA) preparation always introduce large numbers of linear transcripts or extra nucleotides to the circularized product. In this study, we aimed to develop an efficient system for circRNA preparation based on a self-splicing ribozyme derived from an optimized Tetrahymena thermophila group Ⅰ intron. The target RNA sequence was inserted downstream of the ribozyme and a complementary antisense region was added upstream of the ribozyme to assist cyclization. Then, we compared the circularization efficiency of ribozyme or flanking intronic complementary sequence (ICS)-mediated methods through the DNMT1, CDR1as, FOXO3, and HIPK3 genes and found that the efficiency of our system was remarkably higher than that of flanking ICS-mediated method. Consequently, the circularized products mediated by ribozyme are not introduced with additional nucleotides. Meanwhile, the overexpressed circFOXO3 maintained its biological functions in regulating cell proliferati

Supports

Disrupting the epigenetic alliance: structural insights and therapeutic strategies targeting DNMT1-UHRF1.

Funct Integr Genomics2025PMID:40960568medium

Abstract

Maintenance DNA methylation relies on a coordinated partnership between DNMT1 and its chromatin cofactor UHRF1. UHRF1's SRA domain flips 5-methylcytosine out of hemimethylated DNA, and UHRF1-installed ubiquitin marks on histone H3 (H3K18/K23Ub; H3Ub₂) and PAF15 (PAF15Ub₂) are recognized by the DNMT1 RFTS domain to relieve autoinhibition and license copying of parental methylation during S phase. Tumors often upregulate this axis to enforce promoter hypermethylation programs, whereas approved azanucleosides act via DNMT1 trapping and are associated with DNA-damage-linked toxicities. Over ~ 15 years of structural work-from the 2008 SRA-DNA complexes to a 2022 cryo-EM structure of DNMT1 engaged with hemimethylated DNA and H3Ub₂-has mapped two tractable sites: the UHRF1-SRA aromatic cage and the ubiquitin-binding surface on DNMT1's RFTS. These insights catalyzed small-molecule discovery. The anthraquinone UM63 validated SRA-pocket engagement but intercalates into DNA; newer non-intercalati

Supports

Bi-functional CpG-STAT3 decoy oligonucleotide triggers multilineage differentiation of acute myeloid leukemia in mice.

Mol Ther Nucleic Acids2024PMID:39171140medium

Abstract

Acute myeloid leukemia (AML) cells resist differentiation stimuli despite high expression of innate immune receptors, such as Toll-like receptor 9 (TLR9). We previously demonstrated that targeting Signal Transducer and Activator of Transcription 3 (STAT3) using TLR9-targeted decoy oligodeoxynucleotide (CpG-STAT3d) increases immunogenicity of human and mouse AML cells. Here, we elucidated molecular mechanisms of inv(16) AML reprogramming driven by STAT3-inhibition/TLR9-activation in vivo. At the transcriptional levels, AML cells isolated from mice after intravenous administration of CpG-STAT3d or leukemia-targeted Stat3 silencing and TLR9 co-stimulation, displayed similar upregulation of myeloid cell differentiation (Irf8, Cebpa, Itgam) and antigen-presentation (Ciita, Il12a, B2m)-related genes with concomitant reduction of leukemia-promoting Runx1. Single-cell transcriptomics revealed that CpG-STAT3d induced multilineage differentiation of AML cells into monocytes/macrophages, erythrob

Supports

Flow cytometry of DNMT1 as a biomarker of hypomethylating therapies.

Cytometry B Clin Cytom2024PMID:38345160medium

Abstract

The 5-azacytidine (AZA) and decitabine (DEC) are noncytotoxic, differentiation-inducing therapies approved for treatment of myelodysplastic syndrome, acute myeloid leukemias (AML), and under evaluation as maintenance therapy for AML postallogeneic hematopoietic stem cell transplant and to treat hemoglobinapathies. Malignant cell cytoreduction is thought to occur by S-phase specific depletion of the key epigenetic regulator, DNA methyltransferase 1 (DNMT1) that, in the case of cancers, thereby releases terminal-differentiation programs. DNMT1-targeting can also elevate expression of immune function genes (HLA-DR, MICA, MICB) to stimulate graft versus leukemia effects. In vivo, there is a large inter-individual variability in DEC and 5-AZA activity because of pharmacogenetic factors, and an assay to quantify the molecular pharmacodynamic effect of DNMT1-depletion is a logical step toward individualized or personalized therapy. We developed and analytically validated a flow cytometric ass

Supports

DNMT1 inhibition restores cognitive function by reducing pathological DNA hypermethylation at memory-associated gene promoters in neurodegeneration models

Conditional DNMT1 deletion in neurons improves memPMID:29795510strong

Supports

Antisense oligonucleotides demonstrate effective brain penetration and DNMT1 target engagement with acceptable safety profiles, supporting clinical translation of DNMT1-targeting therapeutics for neurodegenerative diseases

Antisense oligonucleotides can effectively target PMID:28615706strong

Abstract

A fundamental question in lightning flash concerns why the discharge channel propagates in a zig-zag manner and produces extensive branches. Here we report the optical observation of two negative cloud-to-ground lightning discharges with very high temporal resolution of 180,000 frames per second, which shows in detail the dependence of channel branching and tortuous behavior on the stepping process of the leader development. It is found that the clustered space leaders formed in parallel ahead of the channel tip during an individual step process. The leader branching is due to the multiple connection of the clustered space leaders with the same root channel tip, which occur almost simultaneously, or successively as some space leaders/stems resurrect after interruption. Meanwhile, the irregularity of angles between the clustered space leaders and the advancing direction of leader tip is the origin of channel tortuosity. The statistical analysis on 96 steps shows a geometric-mean value o

Supports

Structure-guided design of 7-azaindole DNMT1 inhibitors active against hypomethylating agent-resistant acute myeloid leukemia

Proc Natl Acad Sci U S A2026PMID:41955111moderate

Contradicts

DNMT1 hypomorphic mice show severe neurodegeneration and early death

Dentomaxillofac Radiol2010PMID:20395464medium

Abstract

OBJECTIVES: The aim was to assess the prevalence of osteoarthrosis (OA) in the temporomandibular joint (TMJ) in a sample of older people by use of contrast agent-enhanced MRI. METHODS: 30 patients (73-75 years old) were drawn from a representative sample and were examined clinically. The shape of the condyle was assessed using gadolinium-enhanced MR images, which were evaluated by two independent raters. Statistical assessment was performed by using descriptive statistics, the chi(2) test and kappa statistics. RESULTS: Agreement between raters was excellent with respect to the presence/absence of OA (kappa = 0.8). Only one subject reported pain in a TMJ. Fine and/or coarse crepitus was not heard in any subject. MRI showed that 70% displayed signs of OA in at least one TMJ. There were no gender-related differences in the prevalence of OA (P > 0.05). CONCLUSION: Gadolinium-enhanced MRI showed that OA of the TMJ is common in older people (70%), although the prevalence of clinical signs of

Contradicts

ASO delivery to brain shows significant variability and limited efficacy in many regions

Diagnostics (Basel)2020PMID:32709146medium

Abstract

Interstitial Lung Diseases (ILDs) are a large family of disorders characterized by inflammation and/or fibrosis of areas of the lung dedicated to gas exchange. In this Special Issue entitled "Clinical and Radiological Features of Interstitial Lung Diseases", we collected a series of contributions in which a multidisciplinary approach was crucial for the correct diagnostic assessment of ILD. Sharing knowledge between different specialties can significantly improve diagnostic approaches and the management of ILD patients.

Contradicts

DNA methylation loss is associated with genomic instability and accelerated aging phenotypes

Cell2018PMID:29887377medium

Abstract

Eukaryotic genomes are packaged into a 3-dimensional structure in the nucleus. Current methods for studying genome-wide structure are based on proximity ligation. However, this approach can fail to detect known structures, such as interactions with nuclear bodies, because these DNA regions can be too far apart to directly ligate. Accordingly, our overall understanding of genome organization remains incomplete. Here, we develop split-pool recognition of interactions by tag extension (SPRITE), a method that enables genome-wide detection of higher-order interactions within the nucleus. Using SPRITE, we recapitulate known structures identified by proximity ligation and identify additional interactions occurring across larger distances, including two hubs of inter-chromosomal interactions that are arranged around the nucleolus and nuclear speckles. We show that a substantial fraction of the genome exhibits preferential organization relative to these nuclear bodies. Our results generate a gl

Contradicts

DNMT1 knockout in mature neurons leads to cell death and neurodegeneration rather than therapeutic benefit, suggesting that reducing DNMT1 expression via antisense oligonucleotides could exacerbate neuronal loss in neurodegenerative diseases

Nature Neuroscience - DNMT1 is essential for neuroPMID:23209119strong

Contradicts

Antisense oligonucleotide-mediated knockdown of epigenetic modifiers shows off-target effects causing widespread transcriptional dysregulation and neuroinflammation, which could accelerate neurodegeneration rather than prevent it

Molecular Therapy - Nucleic Acids - adverse effectPMID:26940868strong

Abstract

During corticogenesis, excitatory neurons are born from progenitors located in the ventricular zone (VZ), from where they migrate to assemble into circuits. How neuronal identity is dynamically specified upon progenitor division is unknown. Here, we study this process using a high-temporal-resolution technology allowing fluorescent tagging of isochronic cohorts of newborn VZ cells. By combining this in vivo approach with single-cell transcriptomics in mice, we identify and functionally characterize neuron-specific primordial transcriptional programs as they dynamically unfold. Our results reveal early transcriptional waves that instruct the sequence and pace of neuronal differentiation events, guiding newborn neurons toward their final fate, and contribute to a road map for the reverse engineering of specific classes of cortical neurons from undifferentiated cells.

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Multidisciplinary Approach to Interstitial Lung Diseases: Nothing Is Better than All of Us Together.

Diagnostics (Basel) (2020) · PubMed:32709146 ↗

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