DNA methylation patterns in juvenile systemic sclerosis and localized scleroderma.

Area of Science:

• Immunology
• Epigenetics
• Genomics

Background:

• Scleroderma encompasses chronic fibrotic immune-mediated diseases with unknown causes.
• Epigenetic alterations in childhood-onset scleroderma subtypes remain largely uncharacterized.
• Understanding these changes is crucial for diagnosing and treating juvenile systemic sclerosis (jSSc) and juvenile localized scleroderma (jLS).

Purpose of the Study:

• To investigate and compare DNA methylation differences and similarities between jSSc and jLS patients and healthy controls.
• To identify potential epigenetic biomarkers for distinguishing between these conditions.
• To explore the functional implications of observed epigenetic changes.

Main Methods:

• Genome-wide DNA methylation analysis using the MethylationEPIC array on peripheral blood mononuclear cells (PBMCs).
• Bioinformatic analysis to identify differentially methylated sites and genes.
• Canonical pathway analysis to understand enriched biological processes.

Main Results:

• Identified 105 differentially methylated sites in jSSc and 144 in jLS compared to controls.
• Observed largely unique epigenetic patterns for jSSc and jLS, indicating distinct disease mechanisms.
• Discovered a specific CpG site in FGFR2 capable of accurately distinguishing localized scleroderma (LS) from healthy PBMCs.
• Enriched inflammatory pathways (STAT3, NF-κB, IL-15) in jSSc and the HIPPO signaling pathway in jLS.
• Suggested a role for NOTCH3 in both conditions and identified unique transcription factors for each.

Conclusions:

• Juvenile systemic sclerosis and juvenile localized scleroderma exhibit distinct epigenetic profiles.
• Epigenetic modifications, particularly DNA methylation, offer insights into the pathogenesis of these diseases.
• A potential novel epigenetic diagnostic biomarker for localized scleroderma was identified, warranting further investigation.