Epigenetics Beyond the Clinic: A New Journal Charts the Field’s Next Frontier

Epigenetics, the study of molecular machinery that controls gene activity without altering the underlying DNA sequence, has grown from a niche discipline into one of the most dynamic areas of modern biology. Yet according to Lucia Altucci of the University of Campania Luigi Vanvitelli in Naples and Marianne G. Rots of the University of Groningen, the field still lacks a dedicated home for the kind of fundamental, cross-disciplinary work that does not yet carry direct clinical implications. Writing in the inaugural editorial of Epigenetics Communications, a new open access journal launched as a companion to Clinical Epigenetics, the two editors-in-chief lay out both the promise and the unresolved puzzles of a science that operates, as they put it, above the genome.

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