The opening keynote set an ambitious tone. Wendy Bickmore, director of the MRC Human Genetics Unit at the University of Edinburgh and a pioneer in functional three-dimensional genome organization, delivered the special EMBO Keynote lecture on how the non-coding genome regulates gene activity. She illustrated that distant enhancers do not always need direct physical contact with their target promoters to activate gene expression, but they must be located within roughly 200 to 300 nanometers of a promoter to function effectively. Bickmore showed that cohesin-mediated loop-extrusion is essential for long-range enhancer action, while also challenging the loop-extrusion model as the sole explanation, presenting evidence from her laboratory of ‘leaky’ insulation across topologically associating domain boundaries that causes bystander activation. She also unveiled a novel histone post-translational modification, H3K115 acetylation, which sits within the histone core rather than on the tail and is enriched precisely at the transcription start site in the nucleosome-depleted region, suggesting it marks a fragile nucleosome strongly associated with active transcription.

On the second day, Lei Stanley Qi, associate professor of bioengineering at Stanford University and a pioneer in CRISPR technology, offered a conceptual reframing of how scientists should interpret chromatin maps. TAD boundaries, he argued, are merely snapshots of chromatin interactions, whereas a cell functions as a living, dynamic system. He drew an evocative parallel with Leonardo da Vinci’s Vitruvian Man, which captures optional configurations of the human body, much as epigenetic figures capture the states of many cells across time and space. Qi described an epistasis mapping approach to enhancer functionality, explaining how redundant, independent, or synergistic enhancer interactions can provide compensatory, fine-tuning, or robust regulatory effects respectively, and noted that BRD4-mediated condensation can facilitate such interactions. Notably, his findings independently confirmed Bickmore’s conclusion that enhancers need spatial proximity to promoters to exert their effects.

The final keynote, from Angelo Lombardo, professor of tissue biology and regenerative medicine at Vita-Salute San Raffaele University and co-founder of Chroma Medicine, delivered perhaps the strongest evidence yet that epigenetic editing can work as a durable therapy. His laboratory discovered that stable gene repression requires simultaneous methylation of DNA and repressive histone marks, and that epigenetic regulators such as DNMT3A/3L and KRAB domains, which catalyze DNA and histone methylation, silence retroviral elements in embryonic stem cells. Inspired by this natural system, the group fused DNMT3A/3L and the KRAB domain of ZNF10 to zinc finger domains targeting specific genomic regions, achieving stable gene repression across multiple cell lines. They recently demonstrated long-term repression of PCSK9, a hepatocyte gene involved in cholesterol homeostasis, in mice for nearly one year, reducing LDL receptor presence on hepatocyte membranes. Strikingly, even after partial liver resection, the induced DNA methylation state and repressed expression were retained in the regrown tissue, showing that these modifications are faithfully inherited. Lombardo also highlighted epigenetic silencing of Hepatitis B virus via induced DNA methylation as a viable therapeutic avenue.

Beyond the keynotes, a wave of technical innovation is reshaping how epigenetic enzymes are understood and improved. Albert Jeltsch of the University of Stuttgart uses Deep Enzymology to systematically investigate the preferred flanking DNA sequences of DNA methyltransferases, finding that different DNA substrates influence DNMT1 efficacy so drastically that allele-specific DNA methylation becomes possible. Saulius Klimašauskas and colleagues at Vilnius University developed a click-chemistry technique for bioorthogonal labeling at sites where individual DNMTs catalyze methylation in live cells, enabling high-resolution chemical ‘tracks’ of epigenetic writers throughout the cell cycle. At Rice University, Jacob Goell reduced the cytotoxicity of the histone acetyltransferase P300 while preserving its enzymatic activity through a single point mutation in the P300 core, and found that P300 primes genes for activation and enhances prime editing efficiency independently of its catalytic function.

Epigenetic reader domains, which evolved over millions of years to recognize specific post-translational modifications, are also becoming central tools, particularly where high-quality antibodies are hard to develop. Tuncay Baubec of Utrecht University presented ChromID, a systematic approach in which a biotin ligase fused to a chromatin reader domain biotinylates nearby proteins; after pull-down and mass spectrometry, the epigenetic proteome at a targeted modification is mapped. EpiCypher’s Matthew Meiners described chimeric tandem reader domains and synthetic, fully chemically defined modified nucleosomes for use as spike-ins in CUT&RUN and CUT&Tag assays, allowing researchers to map reader-PTM interactions and histone modification co-occurrences. Anja Köhler of the University of Stuttgart introduced the Bimolecular Anchor Detector, or BiAD, technology, which combines a sgRNA/dCas9 DNA-binding module with reader-domain detector modules fused to complementary split fluorophore parts, reconstituting fluorescence only when both modules bind in proximity, thereby visualizing epigenetic marks at specific genomic loci in living cells. Meanwhile, Marvin Tanenbaum of the Hubrecht Institute presented stopless-ORF circular mRNAs encoding SunTag epitopes, permitting live-cell single-molecule imaging of ribosome kinetics and revealing that ribosome collisions actually facilitate translation through difficult sequences by resolving stalls.

As the toolbox expands, so does the appetite for unbiased, high-throughput screening. Lacramioara Bintu’s laboratory at Stanford developed dCas9-mediated high-throughput recruitment, or HT-recruit, testing more than 5,000 nuclear protein Pfam domains of human and viral origin for their ability to silence or activate gene expression, alongside a library of 114,288 sequences tiling transcription factors and chromatin regulators. Her characterization was memorably vivid: transcriptional activators tend to be ‘greasy acidic noodles with a little salt, pepper and queso,’ rich in acidic and hydrophobic residues interspersed with serine, proline, or glutamine, while repressors come in more flavors, with KRAB domains the best performers across contexts, including a newly identified KRAB from ZNF705F that outperforms the commonly used ZNF10 KRAB. At UC Berkeley, Michael Herschl screened over 50,000 pairs of epigenetic editors, some with catalytic domains up to 6.3 kilobases, using the COMBINE inducible screening platform, identifying editor combinations that impart long-term epigenetic changes and a bidirectional CRISPR perturbation system capable of activating and repressing genes concurrently. A key insight: domains operating in the same or similar pathways show good perturbation synergy, mimicking their natural collaboration. Samuel Reisman of Duke University, in work toward regenerative therapies, screened over 1,600 human transcription factors with CRISPR activation followed by Perturb-seq single-cell RNA sequencing to map the fidelity and subtype-specificity of astrocyte-to-neuron reprogramming.

Computational advances featured prominently as well. Kim Kira Witetzek of Academia Sinica presented ATAC-Mass, which combines isotopic labeling, ion beam imaging at 100-nanometer resolution, and mass cytometry to integrate epigenomics, proteomics, and three-dimensional nuclear imaging at the single-cell level. Jennifer Spangle of Emory University School of Medicine described a chemoenzymatic technique using an L-methionine analogue that converts into a SAM analogue, tagging methylated proteins with a detectable alkyne; the approach resolves mono-, di-, and trimethylation, histidine methylation, and arginine methylation with site specificity, works in vivo and across the blood-brain barrier, and identified 221 proteins with novel methylation sites upon enrichment. Philipp Schnee of the University of Stuttgart showed how 3D molecular dynamics simulations can predict enzyme behavior, enabling the design of a ‘Super-Substrate’ for protein lysine methyltransferases that outcompetes natural substrates with substantially increased specificity. Kimberley Glass of Brigham and Women’s Hospital presented SPIDER, a computational modeling tool that builds gene regulatory networks from DNase-seq, ATAC-seq, or DNA methylation data, prunes false positives using chromatin states, and accurately predicts ChIP-seq transcription factor binding events lacking a corresponding sequence motif, a persistent weakness of older pipelines.

The field’s clinical momentum was matched by growing candor about its risks. Jamie Hackett of EMBL Rome used CRISPR-dCas9 perturbation screens to dissect causal regulatory roles, finding that blocking histone tail acetylation prevents transcriptional activation after H3K4me3 deposition, and that gene permissiveness to epigenetic reprogramming depends on cell type, expressed factors, and DNA sequence. Domitilla del Vecchio of MIT proposed that H3K9me3 causally follows DNA methylation, noting that KRAB alone does not confer long-term memory while DNMT3A does. Bas van Steensel of the Netherlands Cancer Institute used transposon systems to relocate enhancers, promoters, and CTCF sites across a two-megabase window, discovering that enhancers communicate with gene bodies as well as promoters. On safety, Henriette O’Geen of UC Davis showed that hundreds of CpGs retain off-target methylation 24 days after transient editing, particularly at bivalent genes poised for transcription and implicated in oncogenesis, prompting a call for a gold standard for reporting off-target effects; Majid Pahlevan Kakhki of Karolinska Institutet independently reported widespread unintended methylation across nearly all CRISPR-dCas9 tools, including CRISPRoff. In applied settings, Pernette Verschure’s group found transcription burst size predicts gene responsiveness in hormone-sensitive breast cancer, while Gabriella Ficz of Barts Cancer Institute demonstrated ex vivo epigenetic editing of CDKN2B in umbilical cord hematopoietic stem cells, with durable methylation maintained after engraftment in mice and inherited across myeloid and lymphoid lineages. Ivana Parker of the University of Florida, meanwhile, mapped the epigenetic pathways underlying BCG vaccine-induced macrophage activation. Together, the Amsterdam meeting captured a field in confident transition: from conceptual understanding of chromatin’s static architecture to the dynamic, engineered, and increasingly therapeutic manipulation of the epigenome, balanced by a maturing commitment to safety, standardization, and open collaboration between academia and industry.

Subject of Research: Epigenetic editing technologies and their translation from bioengineering innovations toward clinical therapies

Article Title: Bridging bioengineering and epigenetics: from technical innovations to clinical applications

Article References: Jacob, J., van Loosen, Q. C., van den Berg van Saparoea, A. C. H., Sarno, F., & Verschure, P. J. (2024). Bridging bioengineering and epigenetics: from technical innovations to clinical applications. Epigenetics Communications, 4(1), Article 8. https://doi.org/10.1186/s43682-024-00031-x

Image Credits: AI Generated

DOI: 10.1186/s43682-024-00031-x

Keywords: epigenetics, bioengineering, CRISPR, epigenome editing, DNA methylation, chromatin, gene regulation, clinical applications, off-target effects, high-throughput screening, transcription, gene therapy

The round tables were designed around the framework of Responsible Research and Innovation, or RRI, an approach that has gained traction over the past decade in both academia and science policy. Unlike traditional ethical, legal, and social implications research, which treats ethics as an external check on finished technologies, RRI asks scientists to embed social and ethical reflection into the earliest stages of research itself. This is no small ask. Studies cited in the report show that many natural scientists see themselves as responsible only for the quality of their research, viewing societal consequences as the domain of regulators and oversight bodies operating downstream in a linear model of innovation. The term responsibility, researchers have found, can even be perceived as accusatory by scientists who feel that RRI policies are imposed by outsiders unfamiliar with the realities of laboratory work.

To avoid these pitfalls, the organizers built the discussions around two concrete case studies tailored to the actual technical frontiers of epigenetics. Ten tables of roughly eight participants each, moderated and blended across seniority, gender, and research interests, spent forty minutes debating guided vignettes before their note-takers submitted minutes for thematic analysis. The first case examined whether epigenetic editing, a nascent family of technologies that rewrites gene expression without altering the DNA sequence, is ready to move from bench to bedside. The second probed whether environmental epigenetics, the study of how exposures shape chemical tags on the genome, is mature enough to inform regulatory risk assessment of chemical safety.

The clinical case centered on a striking proof-of-principle published in Nature in 2024. Using lipid nanoparticles to deliver a so-called hit-and-run epigenetic editor, researchers silenced the Pcsk9 gene in mice, stably reducing plasma cholesterol for eleven months without the editor persisting in the cells. The promise is obvious: a one-time therapy that could replace daily statin adherence, which is undermined by forgetfulness, side effects, and poor awareness. Round table participants largely agreed that a single-administration therapy would be preferable to recurrent medication, provided safety and efficacy standards were met. Yet the conversation quickly grew more complicated. One group argued that epigenetic editing should only become a standard treatment if it offers clear additional benefits over existing drugs. Others questioned the economics, noting that the global statin market was valued at over sixteen billion dollars in 2023 and suggesting that biotechnology companies may simply be eyeing a shift of pharmaceutical profits rather than genuine cost savings for patients.

Beneath the commercial questions lay deeper scientific uncertainties. Participants agreed that knowledge of the long-term and off-target effects of epigenetic editing is far too thin for clinical deployment. Delivery of synthetic editors into cells remains problematic, and little is known about how editing behaves differently across cell types. Stability of the induced modifications, a precondition for any durable therapy, has been demonstrated only in limited windows, and cells may well fight back to restore their original epigenetic state, potentially requiring regular epigenome and transcriptome monitoring. Reversibility is equally underexplored, yet participants considered it essential: clinicians would need the ability to revert cells to their original state should severe side effects emerge. Some groups raised the specter of cancer or autoimmune responses, and while a few speculated about impacts on future generations, the participants emphasized that no consensus exists on intergenerational epigenetic inheritance in humans.

The discussions also surfaced concerns about equity and biological complexity. Without diverse reference epigenomes, widespread therapeutic editing could accrue existing health inequalities, a risk participants proposed to mitigate through more diverse basic research, representative clinical trials, and parallel development of alternative treatments. Two groups cautioned against simplistic views of safety, warning that even an on-target edit could trigger a domino effect through regulatory networks, with downstream consequences for genes far removed from the intended target. Yet one participant pushed back with a pointed rhetorical question about a double standard: do we know the on-target systemic effects of aspirin, and if not, why should epigenetic technologies be held to a stricter evidentiary bar than established drugs? In an unprompted turn, several groups also discussed public outreach, worrying that patients might be frightened by the phrase gene editing and suggesting the technology may even need a new name.

The second case, on environmental epigenetics and chemical regulation, produced an even more sobering assessment. Participants from six tables found common ground that current epigenetic evidence is not ready to support the regulation or prohibition of substances. There are no known unique epigenetic signatures for specific exposures, and the same stress response can be triggered by different chemicals, making it nearly impossible to dissect the contribution of any single component of a person’s exposome. No standardized methods exist to establish what minimal epigenetic change can be meaningfully interpreted as functional disease risk, so results are hard to interpret and difficult to reproduce. Tissue access compounds the problem: researchers can mostly measure blood, swabs, urine, and feces, even though organs like the brain, highly relevant to stress research, remain inaccessible, and different tissues react differently to chemicals. Animal models offer only limited translational value because of differing lifespans and epigenetic drift.

Challenges inherent to epigenetic biology itself deepened the pessimism. Genetic background can confound exposure studies, as illustrated by a 2017 finding that children carrying a common PON1 gene variant showed adverse cardio-metabolic methylation profiles only when prenatally exposed to pesticides, implying that identical exposures produce different risk profiles depending on the individual. Route of intake, dose chronology, exposure windows from pregnancy to old age, and interacting contexts like the microbiome, diet, and socioeconomic status all modulate epigenetic effects, which are themselves small against multifactorial disease backgrounds. Participants questioned whether statistical epigenetic data would even add value beyond existing epidemiological correlations, and they flagged societal risks of their own science: stigmatization of prospective parents, echoing what pregnant smokers already face, and the potential misuse of epigenetic data by insurers, a scenario participants urged governments to regulate proactively. As a path forward, groups called for standardized methods, large prospective cohorts, bioinformatic integration of heterogeneous data, and honest debate about whether the community has a responsibility to push epigenetic testing into regulatory science, even as the tobacco saga shows policymakers can resist decades of harm evidence.

Perhaps the report’s most striking finding is the divergence of views on what all this means for translation. One camp sees the field’s immaturity as a solvable practical challenge, pointing to accumulating safety data on editing platforms and the slow advance of epigenetic endpoints in toxicology. A second, more cautious group doubts that data harmonization and standardization can ever fully succeed. A third views the complexity of the epigenome, shaped by environment, stochasticity, and gene-environment interplay, as a fundamental barrier that no methodology will overcome, rendering cause-and-effect disentanglement effectively impossible. Meanwhile, a few participants questioned whether demanding complete knowledge before translation is an unreasonable standard at all, noting that two epigenetic editing clinical trials have already received medical-ethical approval. The authors tentatively attribute these splits to differences between basic and translational researchers, to hype dynamics driven by venture capital, and to competitive pressures in the market economy.

From these tensions, the report’s authors extract a three-part agenda. First, the field must explicitly discuss what kinds of knowledge it deems necessary before clinical or regulatory translation, openly interrogating how much of the rush toward epigenetic innovation reflects informed judgment versus hype and a race for startup capital. Second, widely accepted methodological and analytical standards are needed to bridge basic science and application, a mission the International Society for Molecular and Clinical Epigenetics has begun promoting through interdisciplinary dialogue. Third, and most notably, the round tables revealed a largely untapped reflexivity among scientists, who are fully aware of the tension between complete mechanistic understanding and pragmatic innovation, yet rarely given structured forums to confront it. The CLEPIC round tables will become a regular conference feature, and the authors argue that such collaborative spaces, where natural and social scientists interrogate assumptions together, are an essential first step toward responsible epigenetic research and innovation, with reflexivity working in both directions.

Subject of Research: Societal and ethical readiness of epigenetic editing for clinical use and environmental epigenetics for regulatory risk assessment

Article Title: Meeting report on the round table discussions ‘epigenetics and society’ CLEPIC24

Article References: Habets, M. G., Rots, M. G., & Chiapperino, L. (2025). Meeting report on the round table discussions ‘epigenetics and society’ CLEPIC24. Epigenetics Communications, 5(1), Article 4. https://doi.org/10.1186/s43682-025-00035-1

Image Credits: AI Generated

DOI: 10.1186/s43682-025-00035-1

Keywords: epigenetics, epigenetic editing, responsible research and innovation, environmental epigenetics, precision environmental health, personalized medicine, chemical risk assessment, DNA methylation, CLEPIC24, science policy, statins, PCSK9

One of the most striking conceptual advances came from Paola Scaffidi of the European Institute of Oncology in Italy, who introduced a systems-level framework for understanding epigenetic regulation in cancer. She described the epigenetic regulatory network, or ERN, as the collective assembly of epigenetic modifications that drive cellular states, with individual regulators ranging from dispensable to absolutely essential for cell survival. In healthy cells, this network is built with substantial functional redundancy, so the loss of one or a few components is generally tolerated through compensatory mechanisms. But when oncogenic drivers are added to the mix, the network becomes fragile. Scaffidi presented evidence that cancer cells globally lose roughly 30 percent of their epigenetic regulators, producing aberrant transcriptional responses to stress and an enhanced adaptive capacity compared with normal cells. Many of these losses are subclonal and take on stage-specific roles as tumours evolve, a finding that reframes epigenetic instability not simply as collateral damage but as a potential vulnerability that therapies could exploit.

Chromatin dynamics occupied centre stage throughout the meeting. Karl Ekwall of the Karolinska Institute in Sweden explored how chromatin-modifying enzyme complexes govern cell cycle kinetics in yeast and human fibroblast models, identifying these complexes as essential regulators of quiescence induction when cells face nutrient deprivation. Notably, in vitro analyses showed that targeting these complexes with ouabain, an inhibitor of the LEO1 component, altered LEO1 expression in tumour models but not in normal human fibroblasts, hinting at a therapeutic window for oncology. Geneviève Almouzni of the Curie Institute in France closed the conference with a keynote on chromatin integrity and histone variants, explaining how the replicative histone H3.1, enriched at late-replicating regions, and the variant H3.3, enriched at actively transcribed early-replicating regions, demarcate replication initiation zones with remarkable precision. Her presentation detailed how aberrant histone H3 function, whether through mutation of the protein itself or of chaperone proteins such as DAXX/ATRX, ASF1, CENP-A, HJURP and HIRA, contributes to cancer and other diseases, including evidence that restoring the chaperone HIRA can rescue defective H3.3 deposition patterns.

Cancer epigenetics featured prominently, with complementary sessions probing histone mutations, DNA methylation, transcription factors, chromatin topology and even the tumour microbiome. Jonathan Licht of the University of Florida described the contribution of histone fold mutations, which a pan-cancer analysis found in approximately 7 percent of patients, particularly in bladder, oesophageal, head and neck, and skin cancers. The most common of these, H2B E76K, destabilises the H2B/H4 interface, accelerating chromatin degradation into oligonucleosomes and freeing H2A-H2B dimers from the histone octamer. In lung epithelial cell models, this opens up chromatin and ramps up signalling through polycomb-repressed regions, epithelial-mesenchymal transition pathways, and AKT and c-Jun cascades, all of which can promote migration, proliferation, cytokine secretion and resistance to apoptosis.

DNA methylation emerged as a versatile player in cancer progression and diagnosis. Aniruddha Chatterjee of the University of Otago in New Zealand presented work on colorectal cancer showing that conserved aberrations in the DNA methylome discriminate powerfully between matched primary tumours, lymph node metastases and liver metastases. This matters because metastasis drives 90 percent of cancer deaths, yet no purely genetic drivers can fully explain successful metastatic colonisation; epigenetic plasticity appears to supply the adaptability tumours need. His team is using CRISPR-dCas9-based epigenetic editing at key regulatory loci to test whether methylation changes are cause or consequence. On the translational front, early findings suggest DNA methylome profiling of cell-free DNA, combined with artificial intelligence models, could underpin liquid biopsies for colorectal cancer screening. Susan Clark of the Garvan Institute of Medical Research in Australia widened the lens to the three-dimensional genome, describing how mutations at ‘persistent’ CTCF binding sites, which anchor loops and topologically associated domain borders, recur in prostate and breast cancers and may disrupt higher-order chromatin architecture.

In one of the more unexpected twists of the meeting, Maria Rescigno of Humanitas University in Italy connected the microbiome to epigenetics in cancer. Progressive microbial deregulation accompanies tumour development, and in mouse models the loss of the bacterium Faecalibaculum rodentium was reversed by restoring the organism, which reduced tumour growth and number. Intriguingly, F. rodentium produces butyrate as it proliferates, acting as a histone deacetylase inhibitor that epigenetically modulates apoptosis. A phylogenetically similar strain is underrepresented in human advanced adenomas, and in colorectal cancer, intra-tumoural bacteria appear to modulate treatment response through soluble metabolites, or ‘postbiotics’. In the context of anti-PD-1 checkpoint blockade, different bacterial strains produce postbiotics with different effects on HLA class I expression, suggesting postbiotic therapy could help overcome treatment resistance.

Beyond cancer, the meeting showcased epigenetics in ageing and non-malignant disease. Steve Horvath of Altos Labs in the United Kingdom traced the evolution of epigenetic clocks, machine learning algorithms built on DNA methylation patterns at CpG dinucleotides that estimate chronological or biological age. First-generation clocks estimate chronological age, second-generation clocks predict clinical phenotypes and mortality risk, and third-generation clocks aim for multi-species utility. GrimAge, designed to predict time to death, showed predictive value for chronic obstructive pulmonary disease, type 2 diabetes and ischaemic heart disease over 13 years of follow-up. Andrea Fuso of Sapienza University of Rome demonstrated cross-talk between DNA methylation and non-coding RNAs in Alzheimer’s disease, where methylation modulates PSEN1 and miR-29a, which in turn targets BACE1 and the demethylase gene TET1, feeding into amyloid plaque deposition and linking B vitamin status and one-carbon metabolism to neurodegeneration.

Neurodegeneration and cardiometabolic disease drew further epigenetic links. Eran Meshorer of The Hebrew University of Jerusalem showed that organoid models of early Huntington’s disease display global hypomethylation, altered DNMT3A and DNMT3B signatures and methylation ages older than controls. Counterintuitively, the polyglutamine inclusion bodies characteristic of the disease proved protective, with aggregate-forming cells dying at one third the rate of others; the transcription factor ATF3 was implicated, since its knockout prevented inclusion body formation. Melanie Waldenberger of Helmholtz Munich and Marie Loh of Nanyang Technological University in Singapore presented epigenome-wide studies of dyslipidaemia and cardiovascular risk, respectively, both emphasising ethnic diversity. In the Singapore-based HELIOS study of roughly 50,000 adults, 1,926 CpG sites were associated with carotid intima-media thickness in Asian individuals, 91 percent of them irrelevant in European populations, with two sentinel sites showing possible causal roles, underscoring the danger of extrapolating epigenomic findings across ancestries.

The therapeutic frontier was arguably the most electrifying territory of all. José Sardina of the Josep Carreras Leukaemia Research Institute in Spain used targeted DNA methylation to hypermethylate the IL1RN promoter, generating macrophages with aberrant inflammatory responses and transcriptional profiles resembling tumour-resident macrophages. Angelo Lombardo of the San Raffaele-Telethon Institute for Gene Therapy in Italy described an all-in-one zinc finger epigenetic editor delivered by lipid nanoparticles that silenced PCSK9 in vivo for nearly a year, persisting even through liver regeneration, outperforming CRISPR-dCas9 constructs with minimal off-target effects. Related platforms are being developed for durable silencing of hepatitis B virus and, prospectively, CAG length-specific silencing in Huntington’s disease. A round table debated the roadmap to the clinic, highlighting needs for standardised delivery, early regulatory engagement, quality control and stakeholder inclusion, including patients and low- and middle-income countries.

Clinical trials and drug discovery sessions reinforced the momentum. Christophe Le Tourneau of the Curie Institute presented the PEVO basket trial of the HDAC inhibitor vorinostat combined with immunotherapy in recurrent or metastatic squamous cell carcinomas, reporting a median response rate of 26 percent, highest in anal and cervical tumours, with better responses linked to microsatellite instability, HPV positivity and high PD-L1 scores. Emily Dykhuizen of Purdue University described SWI/SNF subcomplex targeting, including BRD9 degraders showing anti-tumour activity through macrophage activation and ARID1A inhibition flipping cold tumours toward immune-infiltrated hot states. Cheryl Arrowsmith of the University of Toronto outlined chemical probe screening revealing context-dependent EZH2 vulnerabilities, while Christoph Bock of CeMM in Austria closed with a vision of epigenetic priming, in which ‘alertness drugs’ could pre-emptively harden innate immunity against infection, and of AI tools such as CellWhisperer that let researchers interrogate sequencing data in plain English. Together, the meeting made clear that epigenetics, once a purely academic curiosity, is now positioned to reshape diagnostics and therapy across medicine.

Subject of Research: Recent advances and clinical opportunities in epigenetics research presented at the 4th Clinical Epigenetics International Conference

Article Title: Clinical epigenetics: recent advances and opportunities

Article References: Smith, J., Chatterjee, A., & Rodger, E. J. (2025). Clinical epigenetics: recent advances and opportunities. Epigenetics Communications, 5(1), Article 7. https://doi.org/10.1186/s43682-025-00038-y

Image Credits: AI Generated

DOI: 10.1186/s43682-025-00038-y

Keywords: clinical epigenetics, epigenetic editing, DNA methylation, chromatin, cancer epigenetics, epigenetic clocks, epigenetic therapeutics, HDAC inhibitors, CRISPR, microbiome, Alzheimer's disease, Huntington's disease

The central obstacle to a cure is the remarkable persistence architecture of the hepatitis B virus. After the virus enters hepatocytes through the NTCP receptor, its relaxed circular DNA genome is repaired by host factors into covalently closed circular DNA, or cccDNA, a stable episomal minichromosome that persists in the nucleus and serves as the transcriptional template for all viral RNAs and proteins. In parallel, fragments of viral DNA integrate at random sites into the host genome as integrated DNA, or intDNA, which does not produce new virus but continuously secretes surface antigen and, in some cases, the oncogenic HBx protein, fueling immune tolerance and carcinogenesis. Current interferon-alpha and nucleos(t)ide analog therapies leave both reservoirs untouched, so viral rebound is common once treatment stops, and long-term nucleos(t)ide therapy carries risks such as nephrotoxicity.

The Groningen team frames the therapeutic landscape around two epigenetic strategies. The first, broad-acting epidrugs, globally modulate histone- and DNA-modifying enzymes; nine such agents are already FDA-approved in oncology. The second, epigenetic editing, fuses effector enzymes to programmable DNA-binding domains — zinc-finger proteins, transcription activator-like effectors, or deactivated CRISPR-Cas9 — to write repressive marks at specific viral loci. Because HBV gene activity on cccDNA is governed by histone acetylation and methylation, with HBx recruiting p300 to boost H3 and H4 acetylation while SETDB1-mediated H3K9me3 and PRMT1-mediated H4R3 methylation repress transcription, the viral minichromosome is an unusually tractable epigenetic target.

Among epidrugs, sirtuin 2 inhibitors have produced the most compelling results. The SIRT2 inhibitor AGK2 reduced HBV DNA, RNA, HBsAg and HBeAg by 15 to 30 percent in vitro and in HBV-transgenic mice without hepatotoxicity, and recent work showed the drug acts by recruiting repressive histone lysine methyltransferases to cccDNA, enriching H4K20me1, H3K27me3 and H3K9me3 while reducing RNA polymerase II occupancy. A more specific allosteric inhibitor, FLS-359, blocked the conversion of rcDNA into cccDNA entirely in primary human hepatocytes when given before infection, cutting cccDNA formation by more than half — though it was ineffective after infection was established, positioning it as a preventive rather than curative agent. Meanwhile, the DNA methyltransferase inhibitor 5-azacytidine reactivated interferon-stimulated genes and sensitized otherwise unresponsive cells to interferon-alpha, but it also raised NTCP expression and HBsAg levels, highlighting the double-edged nature of globally acting agents.

That lack of locus specificity is precisely what epigenetic editing is designed to fix, and the review catalogs five preclinical editing studies organized around two approaches. Indirect editing directs a Krüppel-associated box, or KRAB, repressor domain to key HBV regulatory elements; KRAB acts as a scaffold recruiting histone deacetylases, lysine methyltransferases and heterochromatin proteins to shut down transcription. Direct editing instead guides DNA methyltransferases such as DNMT3a or the bacterial M.SssI enzyme to CpG islands overlapping viral promoters, writing de novo methylation that can be mitotically inherited. Both routes reduced HBV RNA, DNA and antigens from cccDNA and, in some contexts, from intDNA, with far better specificity than epidrugs.

The zinc-finger platform, the most rigorously studied to date, illustrates both the promise and the limits. Zhao and colleagues built a six-finger ZFP-KRAB artificial transcription factor targeting the X gene enhancer that cut HBx RNA by roughly 60 percent in Hep3B cells, a line carrying integrated viral DNA. Luo and colleagues achieved the most durable result, with HBV DNA falling to about one-third of control levels in transgenic mice by day seven and remaining significantly lower at day 28, although HBsAg was unchanged. The direct approach by Xirong and colleagues, fusing DNMT3a to a ZFP targeting the X promoter CpG island, lowered HBsAg by 58 percent in mice and 90 percent in cells, with confirmed methylation at seven CpG sites — but the effect reversed by day 20, likely through passive or TET-mediated demethylation. A single TALE-based study by Bloom and colleagues delivered the fastest repression, cutting HBsAg and HBV RNA by 80 percent in Huh7 cells within 48 hours and by 80 to 95 percent in mice within five days, though attribution to KRAB was complicated by the absence of a TALE-only control.

The dCas9 platform, which replaces costly protein engineering with inexpensive single-guide RNAs, is now moving fastest toward patients. The only peer-reviewed dCas9 data for HBV come from a doctoral thesis by Rendón, who fused M.SssI to dCas9 and targeted the conserved CpG islands adjacent to the C and S gene promoters, achieving 2 to 15 percent increases in methylation that downregulated C and S gene transcription but faded within 48 hours. Nevertheless, two clinical trials of dCas9 epigenetic editing for hepatitis B are already underway — NCT06745973 and NCT06671093 — and parallel successes silencing HIV provirus with dCas9-KRAB, plus the demonstration that combined KRAB and DNA methyltransferase editors such as CRISPRoff produce durable, heritable silencing, provide strong proof of concept. Notably, dCas9 editing avoids the genotoxicity risk that shadows nuclease-based CRISPR-Cas9 approaches, whose guide RNAs can partially match human genomic sequences and whose double-strand breaks at the many, variable intDNA loci raise off-target mutagenesis concerns.

Industry has now taken up the challenge with three programs. Tune Therapeutics’ Tune-401, a liver-targeting lipid nanoparticle carrying a guide RNA to CGI2 and mRNA encoding a dCas9 fused to a methyltransferase and an undisclosed repressor, reported 99.99 percent repression of cccDNA-derived HBV RNA in primary human hepatocytes, strong repression of RNA and HBsAg from intDNA in Hep3B cells, epigenetic marks persisting through 275 rounds of cell division over 550 days, minimal off-target effects by RNA-seq, and a favorable safety profile in non-human primates — though these results have not yet been peer reviewed. A Phase 1b trial is recruiting in Hong Kong, Moldova and New Zealand. EpiGENIC’s Epi-003, a similar LNP platform, has entered a Phase 1 trial in China, and nChroma Bio’s CRMA-1001 has shown greater than 99 percent HBsAg reduction sustained for six months in preclinical models. A related Omega Therapeutics trial using LNP-delivered ZFP editors in liver cancer further validates liver-directed epigenetic delivery.

Significant hurdles remain before any of this translates into a functional cure. HBV genomes differ by more than 8 percent at the nucleotide level across genotypes, and the error-prone reverse transcriptase plus the chaotic nature of integration create sequence variability that could blunt editing efficacy, demanding bioinformatic surveillance and possibly personalized designs. Heterochromatin spreading from KRAB editors could silence neighboring host genes at unpredictable intDNA sites, while complete silencing of all antigen sources raises the paradox that eliminating HBsAg might allow exhausted immune cells to miss residual infection, arguing for integration with immune-reactivation strategies. Model limitations compound the problem: primary human hepatocytes rarely form intDNA, Hep3B lacks infection dynamics, and the field needs 3D organoid and humanized mouse systems that capture both reservoirs. Cost and equity loom as well, since most patients live in Southeast Asia and Sub-Saharan Africa while comparable gene therapies have been priced near two million dollars. Still, the authors conclude that with optimized effector combinations, LNP-based hit-and-run delivery — already shown to sustain liver gene silencing for over a year in mice and over 90 days in non-human primates in PCSK9 studies — and clinically relevant models, precision epigenetic editing could deliver what nucleos(t)ide analogs never could: a stable, reversible, non-genotoxic functional cure for chronic hepatitis B.

Subject of Research: Epigenetic editing strategies to silence hepatitis B virus cccDNA and integrated DNA for a functional cure of chronic hepatitis B

Article Title: The promise of epigenetic editing strategies in functionally curing chronic hepatitis B virus infections

Article References: The promise of epigenetic editing strategies in functionally curing chronic hepatitis B virus infections. (n.d.). https://doi.org/10.1186/s43682-025-00041-3

Image Credits: AI Generated

DOI: 10.1186/s43682-025-00041-3

Keywords: epigenetic editing, chronic hepatitis B, hepatitis B virus, cccDNA, integrated HBV DNA, dCas9, zinc-finger proteins, TALEs, KRAB, epidrugs, lipid nanoparticles, functional cure

The study, led by Sophie van Baalen, Thomas Verra and Michelle Habets of the Rathenau Instituut in the Netherlands, together with colleagues at Wageningen University and Erasmus MC, conducted nineteen semi-structured interviews with scientists working in academia and industry between September 2023 and January 2024. Fifteen of the respondents were academic researchers and four worked for commercial companies, with expertise spanning biomedical research, plant science and microbiology. Using snowball sampling and thematic analysis with Atlas.ti software, the team captured the views of researchers across ten European countries and one respondent from the United States, continuing recruitment until no new themes emerged from the transcripts.

The technical logic behind epigenetic editing explains much of its appeal. Unlike CRISPR-Cas9 gene editing, which slices both strands of the DNA double helix to alter the genetic sequence, epigenetic editing tools such as CRISPR-dCas9 and zinc finger proteins bind to specific DNA sequences without cutting them. Instead of changing the letters of the genetic code, they attach or remove chemical marks on the DNA and its associated proteins, dialing gene activity up or down. Because no DNA breaks are introduced, researchers assume the risk of genomic instability is dramatically reduced. Off-target effects, a persistent worry in gene editing, are viewed as less dangerous in the epigenetic version because misplaced edits do not coincide with strand cuts and may fade over time as the cell’s own machinery reverses the marks.

Respondents also described epigenetic editing as fundamentally more subtle than gene editing. Where gene editing acts like a binary switch, introducing or eliminating genetic functions outright, epigenetic editing was compared to a thermostat that fine-tunes the volume of gene expression. Because cells naturally modify their epigenome constantly as part of ordinary biology, scientists framed the technique as working with, rather than against, the cell’s native processes. Several researchers contrasted this precision favorably with epigenetic drugs, a class of therapeutics that targets epigenetic enzymes broadly and is notorious for lacking specificity. One interviewee emphasized the absence of the translocation problems and genetic instability that plague strand-cutting technologies, noting that unlike base editing, prime editing or conventional gene editing, epigenetic editing never cuts the DNA at all.

Yet the same scientists who endorsed this dominant vision simultaneously questioned its foundations, sometimes without being prompted. The reservations clustered around three scientific uncertainties: reversibility, heritability and complexity. On reversibility, researchers acknowledged that while a limited number of studies have shown epigenetic edits can be reversed or remain stable, it is currently impossible to predict whether an edit at a particular genomic location will persist or vanish, and for how long. This creates an awkward paradox, because the stability needed for durable medical treatments and agricultural applications is exactly what undermines the promised safety net of reversibility. As one respondent explained, scientists do not really know what makes some epigenetic modifications stick around for years while others disappear within days, and following patients long enough to find out would require decades-long cohort studies.

Heritability raised equally thorny questions. For epigenetic editing to work in medicine or agriculture, edits must survive cell division, a property called mitotic heritability, and respondents disagreed about whether they reliably do. The possibility of intergenerational and transgenerational inheritance troubled some biomedical researchers, who worried about unintended effects on the offspring of treated patients, while some plant scientists actually counted on epigenetic edits fading out over generations, reasoning that edited crops escaping into the wild would lose their modifications naturally. The third concern, complexity, struck at the heart of the technology’s predictability. Gene expression is governed by intertwined networks in which cause and effect are not linear; altering an epigenetic mark at one location can trigger cascades of unforeseen changes across hundreds of other genes, especially when the three-dimensional folding of DNA and crosstalk between cells enter the picture. One respondent noted that outside of genomic imprinting, they could not think of a single epigenetic network that is well enough characterized to guarantee a clear therapeutic output.

Despite these doubts, three distinct visions of the technology’s medical future emerged among respondents. The prevailing outlook was hopeful but modest: epigenetic editing could eventually treat cancers driven by epigenetic changes, boost the effectiveness of CAR-T immunotherapies, and address rare diseases caused by epimutations, with early clinical trials restricted to patients who have exhausted all other options. Some argued that medicine routinely advances without fully understanding a drug’s mechanism, so demanding perfection before testing would mean never developing the therapy at all. At the cautious extreme, a minority, particularly basic researchers outside translational work, warned that epigenetic editing could prove less safe than gene editing, since introducing epimutations might reactivate dormant transposons or derail cellular identity in ways scientists can no longer control once edited cells are inside the body. At the opposite pole, a small group envisioned a medical revolution in which epigenetic editors retune multiple genes simultaneously, potentially transforming treatment of autoimmune disease, diabetes, Alzheimer’s and even aging, with speculative applications ranging from skin-rejuvenating creams to cures for HIV and chronic hepatitis B.

The agricultural picture diverged sharply. Plant scientists interviewed for the study did not consider epigenetic editing a commercially viable breeding technology, largely because seed companies require traits that remain stable across generations and environmental conditions, from the controlled greenhouse to the unpredictable open field. Backcrossing can eliminate unwanted off-target changes in plants, removing one of epigenetic editing’s main selling points. Still, respondents sketched hypothetical applications that could eventually prove transformative, such as plant varieties that switch on disease-resistance genes only when a pathogen is actually present, or epigenetic control of flowering, which could dramatically shorten breeding cycles for seed production.

The study’s timing makes its findings particularly pointed. While most respondents questioned whether the technology is ready for real-world deployment, companies are already racing ahead: OMEGA Therapeutics completed a first-in-human clinical trial using epigenetic editing to suppress the oncogene c-MYC in twenty-four participants before filing for bankruptcy in early 2025, and Tune Therapeutics is currently recruiting patients for a trial of an epigenetic silencing therapy for chronic hepatitis B. The authors highlight a mismatch between the private sector’s focus on common, profitable conditions such as high cholesterol and obesity, exemplified by celebrated preclinical results showing durable cholesterol reduction in mice and primates, and the academic community’s caution. They argue that the dominant safety narrative is performing rhetorical work, positioning epigenetic editing as publicly acceptable in ways that may prove premature, and warn of a hype-disappointment cycle reminiscent of the gene therapy backlash of the 1990s. The researchers call for explicit reflexivity within the field, public engagement and citizen participation in shaping the technology’s future, and urge scientists to clearly articulate what evidence is truly needed before epigenetic applications move toward the clinic, arguing that making these visions explicit allows scientists, policymakers and the public to reflect on, adapt and co-create the trajectory of this emerging technology rather than simply inherit whatever future the loudest promises deliver.

Subject of Research: Scientific visions, expectations and reservations regarding epigenetic editing and its responsible innovation

Article Title: Visions, expectations, and reservations in epigenetic editing: towards responsible innovation

Article References: van Baalen, S., Verra, T., Macnaghten, P., Bunnik, E., & Habets, M. G. (2026). Visions, expectations, and reservations in epigenetic editing: towards responsible innovation. Epigenetics Communications, 6(1), Article 6. https://doi.org/10.1186/s43682-026-00047-5

Image Credits: AI Generated

DOI: 10.1186/s43682-026-00047-5

Keywords: epigenetic editing, epigenome, CRISPR-dCas9, gene expression, responsible innovation, gene editing, biotechnology, clinical trials, plant breeding, science and technology studies, research ethics, public acceptance