EPITHELIAL EPIGENETICS
Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation to maintain tissue integrity and barrier function. Epigenetic mechanisms provide the molecular framework that governs these processes by regulating gene expression programs that establish and preserve cellular identity. Through dynamic modifications to chromatin, including histone methylation, chromatin accessibility, and enhancer activation, the epigenome enables cells to respond to environmental cues while maintaining stable lineage programs.
Disruption of epigenetic regulation can perturb diverse cellular processes including metabolism, immunity, and tissue repair, ultimately contributing to aging, inflammatory disease, and cancer. Notably, mutations in epigenetic regulators are among the most common alterations in cancers arising from self-renewing epithelial tissues such as squamous cell carcinoma (SCC). SCC represents one of the most prevalent cancers worldwide and can arise across epithelial surfaces including the skin, lung, esophagus, and head and neck. Despite this high frequency, the mechanisms by which epigenetic dysregulation drives epithelial disease remain incompletely understood.
In the Capell Lab, we combine human patient samples, primary cells, and genetically engineered mouse models with cutting-edge genomic technologies, including single-cell, spatial, and epigenomic profiling. to investigate fundamental questions at the intersection of epigenetics, environmental exposure, epithelial biology, immunity, and cancer.
Our work focuses on several major areas:
ENVIRONMENTAL EXPOSURE AND EPIGENETIC MEMORY
The skin is the body’s primary interface with the external environment and is continuously exposed to a complex environmental “exposome” that includes ultraviolet radiation (UVR), air pollution, microbes, chemical irritants, and inflammatory stimuli. Increasing evidence suggests that epithelial tissues do not simply respond transiently to these exposures; rather, they can retain long-lasting epigenetic memories of prior environmental events.
These memories are encoded at gene regulatory elements—particularly enhancers—through persistent changes in chromatin accessibility and histone modifications. Such epigenetic memory programs can shape how epithelial stem cells respond to future exposures, influencing tissue repair, immune responses, and disease susceptibility across the lifespan.
In the Capell Lab, we aim to define how environmental exposures establish, maintain, and distort epigenetic memory within epithelial tissues. Using human disease profiling alongside mechanistic mouse models, we are investigating how exposures such as UV radiation and inflammation reprogram chromatin states and alter epithelial-immune communication. A central goal of this work is to determine whether maladaptive epigenetic memory states that contribute to chronic inflammation or cancer can be therapeutically reprogrammed using targeted epigenetic interventions.
EPITHELIAL–IMMUNE INTERACTIONS
As barrier tissues, epithelia are tightly integrated with the immune system and play a central role in sensing environmental stress and coordinating immune responses. Epigenetic regulation is a key mechanism through which epithelial cells interpret external signals and communicate with surrounding immune and stromal cells.
Our laboratory investigates how epigenetic pathways regulate epithelial-immune crosstalk during tissue homeostasis, inflammation, infection, and tumor development. By integrating spatial transcriptomics, chromatin profiling, and functional genetic models, we seek to understand how epithelial chromatin states influence cytokine signaling, antigen presentation, and immune cell recruitment within the tissue microenvironment.
Understanding these interactions may reveal new strategies to enhance anti-tumor immunity, improve responses to immunotherapy, and restore tissue resilience following environmental stress.
METABOLISM, LIPIDS, AND PROGRAMMED CELL DEATH
Cellular metabolism and chromatin regulation are deeply interconnected. Emerging evidence suggests that metabolic pathways—including lipid metabolism—can directly influence oncogenic signaling, immune responses, and regulated cell death programs.
Our work has identified that key epigenetic tumor suppressors regulate genes controlling lipid metabolism and ferroptosis, a form of iron-dependent programmed cell death that may play a critical role in epithelial differentiation and tumor suppression in SCC.
Because ferroptosis can potentially be modulated through both pharmacologic agents and dietary interventions, this research opens exciting opportunities to develop novel therapeutic approaches that integrate epigenetic regulation, metabolism, and cancer prevention.
SEX CHROMOSOME EPIGENETICS AND SEX BIAS IN DISEASE
Many human diseases display profound sex bias in incidence and outcomes. For example, autoimmune diseases disproportionately affect women, while many cancers, including cutaneous squamous cell carcinoma, occur more frequently and often more aggressively in men.
Despite these well-recognized differences, the biological mechanisms underlying sex disparities in disease remain poorly understood. One emerging contributor is sex chromosome complement, which can influence gene dosage and gene regulation independently of hormonal differences.
Several key epigenetic regulators are encoded on the sex chromosomes, including the X-linked histone demethylase UTX (KDM6A) and its Y-chromosome paralog UTY (KDM6C). Because UTX escapes X-chromosome inactivation, females effectively express higher levels of this epigenetic regulator compared with males.
Using innovative mouse models that separate sex chromosome complement from gonadal sex, along with single-cell and spatial genomic technologies, our lab is investigating how sex chromosome-encoded epigenetic regulators shape epithelial biology, immune responses, and susceptibility to inflammatory and neoplastic disease.
Understanding these mechanisms may ultimately inform the development of sex-specific therapeutic strategies for epithelial diseases.
TOWARD EPIGENETICALLY TARGETED THERAPIES
A central theme of our work is that the epigenome is inherently dynamic and therapeutically reversible. By understanding how chromatin regulators control epithelial identity, environmental memory, and disease susceptibility, we aim to develop strategies that harness epigenetic plasticity to restore healthy tissue states.
Through a combination of genetic models, pharmacologic inhibitors, and emerging epigenome-editing approaches, we are exploring how targeted modulation of chromatin regulators can reprogram disease-associated epigenetic states and improve outcomes in cancer, inflammatory disease, and tissue aging.
If you would be interested in joining our team, please contact us!