The core idea of epigenetics is deceptively simple: chemical tags and structural changes to chromatin, the complex of DNA and proteins in which our genes are packaged, can switch genes on or off, and some of these regulatory networks are reversible while still leaving a form of memory. That combination of plasticity and persistence, the editors argue, underlies the potential of epigenetics to influence physiological and pathological mechanisms across all kingdoms of life. But the simplicity ends there. The regulatory machinery is convoluted, and exploiting the continuously improving genomics technology portfolio, epigenome-wide association studies have produced extensive databases with nucleotide resolution and single cell precision at increasingly affordable costs. These datasets, spanning many organisms, reveal both differences and similarities across species, and integrating them is expected to deepen our understanding of functional epigenomics.

One of the most significant accelerants has been the CRISPR revolution. Nuclease-inactivated Cas9 proteins can now be fused to epigenetic writers or erasers, enzymes that add or remove chromatin marks, allowing researchers to interfere with specific epigenetic modifications at any given chromatin context. According to the editorial, such epigenetic editing studies have already yielded agricultural and preclinical therapeutic successes, alongside the essential scientific insights they provide. The ability to target the epigenome with the same precision that CRISPR brought to genome editing suggests a future in which gene expression itself becomes a programmable therapeutic and biotechnological target.

Yet the editors are candid about the bottlenecks. While individual epigenetic modifications have been mined and functionally studied one by one, the systems and networks they form, and the ways those networks become deregulated, remain far from understood. The intrinsic dynamic nature of chromatin, and the potentially rapid transitions between active euchromatin and silent heterochromatin, still pose formidable technological challenges. Complicating matters further, the so-called epi-players that regulate these transitions switch between chromatin-bound and unbound states, and chromatin modifications show not only rapid state changes but an intrinsic deposition or transition order with functional consequences. Understanding these epidynamic transitions, their spatial deconvolution within the cell, and their impact on genome functioning and organismal adaptation is, the editors write, work that has yet to be done.

That is why the interpretation of the dynamic epigenome and its spatiotemporal organization in different biological systems may prove to be a crucial layer of knowledge in physiology and pathology, from basic research through preclinical and biotechnological applications. Unveiling the networks of epimodulatory events and their precise order, using novel computational methods capable of analysis at the single cell level, holds the key to understanding how gene expression is regulated and how the causal, rather than casual, order of cellular events leads to chromatin organization while preserving the stability and maintenance of cellular function. The study of what the editors call network epigenetics may advance mechanistic understanding of epigenetic dynamics within the three-dimensional structure of cells and tissues, topics that receive dedicated sections in the new journal.

Metabolism adds another layer of complexity. Chromatin epiregulators may take advantage of the abundance of metabolic cofactors, supporting the concept that the availability of those cofactors might determine, to some extent, the prioritization of cellular events. Integrating basic epigenome information with the dynamics and metabolic status of cells, the editors suggest, could bridge fundamental research and preclinical information in the fight against disease. It is a vision of epigenetics as a systems science, one in which chemical marks, three-dimensional genome architecture, metabolic state and time itself are read together rather than in isolation.

The journal also takes a deliberate stance on a problem that has long plagued the field: reproducibility. Given the explosion of epigenetic-based studies, the editors argue it is crucial to distinguish reproducible from irreproducible approaches, and to recognize that technically sound studies can fail to prove a scientific hypothesis without being failures at all. Epigenetics Communications intends to act as a forum for showcasing and discussing alternative conclusions and interpretations of well-established epigenetic phenomena, based on reanalyses of published data or new experiments. The journal welcomes systematic studies whether their outcomes are positive and expected or negative and unexpected, a policy its associate editors greeted with enthusiasm in interviews conducted by Vanessa Tse of the University of Bath.

Several of those editors emphasized how unusual and valuable such a platform is. Karl Ekwall noted that negative results are quite common in research and often hard to publish, and that sharing them saves others in the community from repeating the same experiments. Torsten Plösch observed that many researchers are often afraid of showing results that contradict their expectations, and argued that publishing wrong expectations and negative data is a very important part of the scientific process, helping the field in the same way positive data do. Pernette J. Verschure added a note of caution, pointing out that publishing such data is a new attempt that needs critical reviewing, but that a thorough, well-performed study that contradicts its own hypothesis could turn out to be a genuinely interesting new finding deserving follow-up. Kimberly Glass and Frank Johannes both highlighted the journal’s role in filling a gap for important studies that contribute to understanding epigenetics without yet having specific clinical implications, work that can be used to build something larger with eventual clinical impact.

The associate editors were equally forthcoming about the changing landscape of scientific publishing. On the question of whether preprint servers such as bioRxiv pose a serious challenge to peer review, opinions diverged in interesting ways. Verschure called bioRxiv interesting for its flexibility in putting data out early for comments, but insisted peer review remains critical because researchers cannot keep track of so much data without knowing whether it is trustworthy. Plösch described the current peer review system as not ideal, comparing open commenting platforms to social media and suggesting that honest comments from colleagues are the best way to help authors publish good manuscripts. Ekwall was more emphatic, arguing that anything can be posted on bioRxiv without quality control, that peer review works very well in molecular biology and should not be abandoned, and that expert colleagues can judge quality before publication.

Looking ahead five to ten years, the editors’ associates sketched a field on the cusp of transformation. Glass predicted a recognition of the complexity of biological systems and the need to integrate across different types of data, examining how everything works together to produce networks and emergent properties. Andy Lau anticipated that advances in mass spectrometry and sequencing technologies will continue to reveal novel epimodifications, and that deciphering and manipulating epigenomes might open new avenues in drug design for better treatment of human diseases. Frank Dekker expected data science to play a growing role alongside large epigenome mapping initiatives, yielding new drug targets, new pathways and links to new diseases, and ultimately innovations in diagnosis and therapy. Frank Johannes foresaw the field remaining dominated by technological advances, particularly in single cell epigenomic sequencing assays, which will provide unprecedented insights into functional variation across cell types and development, while dropping sequencing costs allow epigenomic projects to scale up to population level surveys. With its first volume now open, Epigenetics Communications is betting that the next chapter of epigenetics will be written not in isolated discoveries but in the connections between them.

Subject of Research: Epigenetic gene regulation, chromatin dynamics and the launch of a journal for fundamental epigenomics research

Article Title: Epigenetics Communications: where are we?

Article References: Altucci, L., & Rots, M. G. (2021). Epigenetics Communications: where are we?. Epigenetics Communications, 1(1), Article 1. https://doi.org/10.1186/s43682-021-00006-2

Image Credits: AI Generated

DOI: 10.1186/s43682-021-00006-2

Keywords: epigenetics, chromatin, CRISPR epigenetic editing, epigenome-wide association studies, single cell sequencing, network epigenetics, negative results publishing, peer review, bioRxiv, metabolic cofactors, gene expression, Clinical Epigenetics

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