Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis

Area of Science:

• Immunology
• Genetics
• Dermatology

Background:

• Systemic sclerosis (SSc) is characterized by inflammation and fibrosis with limited understanding of its genetic basis and few targeted treatments.
• Current knowledge of SSc pathogenesis offers few insights into effective therapeutic strategies.

Purpose of the Study:

• To investigate the epigenetic mechanisms underlying fibrosis in systemic sclerosis.
• To identify novel therapeutic targets for SSc by exploring the role of TGFB2 signaling.

Main Methods:

• Chromatin accessibility and transcriptome profiling were employed to analyze SSc fibroblasts.
• Targeted epigenetic editing was used to investigate the function of a novel TGFB2 enhancer.
• Inhibition of NF-κB and BRD4 pathways was tested for its effect on TGFB2 activity and fibrosis.

Main Results:

• A previously unannotated TGFB2 enhancer was found to be constitutively active in SSc, maintained by epigenetic memory.
• Autocrine TGFβ2 signaling from this enhancer induced a profibrotic state in patient fibroblasts.
• Inhibition of NF-κB or BRD4 suppressed TGFB2 enhancer activity, reduced profibrotic gene expression, and reversed dermal fibrosis in patient skin explants.

Conclusions:

• Epigenetic dysregulation of TGFB2 represents a potential mechanism driving fibrosis in systemic sclerosis.
• Targeting the NF-κB or BRD4 pathways offers a promising therapeutic strategy for SSc by modulating TGFB2 enhancer activity.