Michael Eyres, Lead Scientist at the Medicines Discovery Catapult (MDC), explores how spatial epigenetics can accelerate biomarker drug discovery.  

Epigenetics, once seen as a cryptic mix of marks on our DNA, is now central to our understanding of gene regulation in health and disease. Until recently, we studied epigenetics only in bulk tissues or single cells. But with emerging techniques that reveal its role within tissue microenvironments, we are entering a new era of biomarker discovery. These breakthroughs will deepen our understanding of how differences across tissues contribute to complex diseases, paving the way for more precise therapies and improved outcomes for people living with conditions that previously had few options. 

Within each of our cells, genes (sequences of DNA) act like instructions for making proteins that perform a wide range of functions. But it is not just the DNA sequence that matters; how these sequences are arranged and tagged determines when and where they are used. 

Epigenetics refers to the study of modifications to DNA and its associated structure (called chromatin), and how these elements influence the way genes are regulated. For example, gene activity can be influenced by how tightly DNA is packaged within cells and how packaged chromatin structures interact with each other.  

Epigenetics enables the hundreds of different cell types in our body to coexist, all while sharing the same DNA sequence. However, in disease, this layer of control often goes wrong. 

Analysis of epigenetics in single cells has advanced drug discovery and development (1) in recent years, providing insight into cell-specific changes implicated in health and disease. But until recently, these changes have been studied in isolation, without considering how individual cells interact within tissues.  

Spatial epigenetics is a transformative new approach that reveals how gene regulation varies across tissue microenvironments. Unlike single-cell approaches, spatial epigenetics enables the study of complex tissues, such as brain tissue in neurodegenerative diseases or scarred tissue in fibrosis, where the mix of cell types and their arrangement play a significant role in how diseases develop and respond to treatment.  

These insights are not only reshaping our understanding of complex and hard-to-study diseases; they are unlocking new avenues for drug discovery that will ultimately improve outcomes for patients.

How do we study epigenetics?

There are two main methods for studying epigenetics.  

Cleavage Under Targets and Tagmentation (CUT&Tag) is a technique used to identify the location of specific DNA-binding factors, and Assay for Transposase-Accessible Chromatin-Sequencing (ATAC-seq) measures the structure of DNA, or how accessible it is for binding factors to bind and influence the activity of genes. Both techniques provide insight into how DNA is modified, packaged and regulated. 

A spatial barcoding approach (developed by AtlasXomics) can also be used to add additional spatial information on top of these methods, allowing us to understand which genes are switched on or what DNA-binding factors are present across the different cells that make up a tissue. 

The spatial barcoding approach works by giving each tiny area of a tissue section its own ‘barcode’, similar to a grid reference on a map. Barcodes are short sequences of DNA and can be applied to specific coordinates across the tissue using microfluidic technology. Later, when scientists analyse the data, they can match the barcode back to the exact spot it came from, alongside the additional information from CUT&Tag and ATAC-seq techniques. This means that they can observe what is happening to genes at near single-cell resolution, within the context of the tissue. 

Comparative studies can then be conducted to understand epigenetic differences across tissues in different conditions or disease states.

How spatial epigenetics accelerates biomarker discovery and target identification

Whilst bulk sequencing methods help provide an ‘average’ of what is happening across a sample, they often overlook subtle but potentially important signals and fail to show the differences between individual cells. Single-cell sequencing methods enable scientists to catalogue individual cells, providing more information, but it is only by adding the spatial element that we are able to study the relationships between these cells and how that influences the genes they express. 

Understanding how epigenetic modifications differ across a tissue enables the discovery of cell – or tissue-location-specific biomarkers that may otherwise be invisible in bulk or single-cell analyses. These biomarkers can reveal how different cells within the same tissue respond to disease or treatment, insight that could help to guide the development of new targeted therapies that act precisely where they are needed.

Case study: Spatial epigenetics in Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a rare and complicated chronic lung disease characterised by increased fibrotic or scar tissue in the lungs, making it difficult for patients to breathe. The disease drastically impacts quality of life, often leaving patients dependent on oxygen therapy and unable to carry out daily activities. Most patients only survive between two and five years post-diagnosis.  

Fibrotic tissue is inherently heterogeneous (made up of lots of different cell types). In IPF, the degree of scarring varies throughout the tissue depth and does not occur uniformly. This makes it challenging to study with bulk or single-cell approaches, and as such, there has been limited innovation in treatment. Currently, there are only two approved medicines to treat IPF, both of which slow disease progression, but there is no treatment that can stop or reverse the scarring of the lungs.  

Spatial epigenetics is opening up new possibilities for treating IPF by helping us understand how genes behave across the different cell types within fibrotic tissue. 

When scientists at Medicines Discovery Catapult and the University of Southampton employed ATAC-seq to compare lung tissue samples from a donor with IPF and a healthy control, it became clear that one region associated with alveolar macrophage genes was highly distinct (2). Further analysis revealed changes in a transcription factor binding site in this region, which became more ‘closed’ or less accessible in IPF, suggesting the genes in this region were less active.  

This analysis presents new potential cell-specific routes for treatment in IPF, and there is hope that further research could lead to a life-changing breakthrough for people with the debilitating condition.

Precision through context

Spatial epigenetics offers a transformative new lens for drug discovery, one that prioritises precision, context, and biological relevance. By integrating spatial molecular data into preclinical workflows, researchers can move beyond one-size-fits-all approaches and toward smarter, targeted therapies that truly reflect the complexity of human disease. This will enable innovators to design therapies that act precisely where needed, reducing off-target effects and improving outcomes for people living with complex conditions and unmet medical needs.  

To truly unlock the next frontier in drug discovery, it is time for the biomedical community to further embrace spatial epigenetics as a core component of translational research. 

About the author

Michael Eyres leads the Spatial Biology team at Medicines Discovery Catapult, leveraging cutting-edge spatial technologies to deepen our understanding of disease and accelerate drug development. 

References:

1: Single-cell technology for drug discovery and development.2024 Frontiers in Drug Discovery. 2024: doi.org/10.3389/fddsv.2024.1459962 Frontiers in Drug Discovery  

2: Spatially resolved deconvolution of the fibrotic niche in lung fibrosis. Cell Rep. 2022 Aug 16;40(7):111230. doi: 10.1016/j.celrep.2022.111230. PMID: 35977489; PMCID: PMC10073410.