Unraveling the epigenetic mechanisms behind chronic inflammatory skin disease
2-3% of population affected by psoriasis
Imagine your body's genetic instructions being fine-tuned by invisible molecular switches that can be flipped on and off. This isn't science fiction—it's the reality of epitranscriptomics, a exciting field exploring how chemical modifications to RNA molecules regulate our biology. Among these modifications, one called N6-methyladenosine (m6A) has emerged as a crucial player in various diseases, including the chronic inflammatory skin condition psoriasis.
Affecting approximately 2-3% of the global population, psoriasis is more than just a skin condition—it's a complex, immune-mediated disorder that causes painful, scaly patches and significantly impacts quality of life 3 .
While scientists have understood the basics of psoriasis inflammation for years, the complete picture of what drives this condition has remained elusive. Recent breakthroughs have now revealed that m6A modifications serve as master regulators of the inflammatory processes that characterize psoriasis, opening exciting new possibilities for understanding and treating this stubborn condition 1 8 .
To appreciate how m6A influences psoriasis, we first need to understand the key players in the m6A regulatory system. Think of m6A as a dynamic code written onto RNA molecules that helps determine their fate and function within cells.
Enzymes that add m6A marks to RNA
Enzymes that remove m6A marks
Proteins that interpret m6A marks
| Component Type | Main Elements | Primary Function |
|---|---|---|
| Writers | METTL3, METTL14, WTAP | Add m6A modifications to RNA |
| Erasers | FTO, ALKBH5 | Remove m6A modifications from RNA |
| Readers | YTHDF1-3, YTHDC1-2, HNRNPC | Recognize m6A marks and execute functional outcomes |
This sophisticated regulatory system allows cells to rapidly adjust gene expression without altering the underlying DNA sequence—a crucial capability in dynamic processes like inflammation and immune response.
The initial clues linking m6A to psoriasis came from transcriptome-wide studies that mapped m6A patterns across the entire landscape of RNA molecules in healthy versus psoriatic skin. Researchers discovered that psoriatic skin lesions exhibit significantly altered m6A methylation patterns compared to both uninvolved psoriatic skin and healthy control skin 8 .
One groundbreaking study revealed that 19.3–48.4% of all differentially expressed transcripts in psoriasis were modified by m6A, establishing a strong connection between m6A modification and the gene expression changes that drive psoriasis 8 .
Findings from specific immune cells 1
This apparent contradiction actually reveals an important truth about m6A regulation: it's cell-type specific. The 2025 study demonstrated that in psoriatic macrophages, METTL3 and m6A modification were upregulated, while the demethylase ALKBH5 was downregulated 1 . This combination creates a perfect storm for excessive m6A accumulation in these specific immune cells.
Researchers created genetically engineered mice where either METTL3 or ALKBH5 could be specifically deleted in macrophage cells.
Used imiquimod (IMQ) to induce inflammation closely resembling human psoriasis in the mouse models.
Evaluated psoriasis severity using PASI scoring, epidermal thickness measurement, immune cell infiltration analysis, and cytokine quantification.
Examined how m6A modifications affect specific target genes and signaling pathways in both mouse and human cell cultures.
| Genetic Manipulation | Effect on m6A | Impact on Psoriasis Symptoms | Effect on Macrophage Polarization |
|---|---|---|---|
| METTL3 Knockout | Decreased m6A | Reduced severity | Inhibited M1 (pro-inflammatory) polarization |
| ALKBH5 Knockout | Increased m6A | Worsened severity | Promoted M1 polarization |
The researchers identified the specific molecular pathway: m6A modifications stabilize Slc15a3 mRNA, which enhances the recruitment of TASL to activate IRF5 signaling—a known driver of inflammation 1 .
Potential m6A-targeting treatments for psoriasis include:
Targeting METTL3 in specific immune cells
Compounds that enhance ALKBH5 activity to reduce excessive m6A
Drugs that interrupt downstream effects of m6A-mediated inflammation
The fact that m6A modifications are reversible makes them particularly attractive drug targets compared to permanent genetic alterations.
The discovery of m6A's role in psoriasis represents a paradigm shift in our understanding of this complex condition. No longer viewed solely through the lens of genetic predisposition or immune dysfunction, we now recognize that epitranscriptomic regulation serves as a critical interface between genetic information and inflammatory outcomes.
Can we target m6A dysregulation in specific cell types?
How does m6A interact with other epigenetic mechanisms?
Can m6A patterns predict treatment response?
What's clear is that the m6A code has fundamentally expanded our understanding of psoriasis pathogenesis. As we continue to decipher this complex regulatory language, we move closer to innovative diagnostics and targeted treatments that may finally provide lasting relief for the millions living with this challenging condition.