KDM6B drives epigenetic reprogramming associated with lymphoid stromal cell early commitment and immune properties

Area of Science:

• Immunology
• Epigenetics
• Cell Biology

Background:

• Lymphoid stromal cells (LSCs) organize immune responses in lymphoid organs.
• Inflammation-driven tertiary lymphoid structures rely on immunofibroblasts.
• Molecular and epigenetic mechanisms of LSC/immunofibroblast commitment remain unclear.

Purpose of the Study:

• To investigate the transcriptomic and epigenetic reprogramming during LSC/immunofibroblast commitment.
• To identify key molecular drivers of immunofibroblast differentiation.
• To explore the role of identified drivers in immune cell recruitment and disease pathogenesis.

Main Methods:

• Transcriptomic analysis of differentiating LSCs/immunofibroblasts.
• Epigenetic profiling to identify key regulators.
• Functional assays to assess KDM6B's role in immunofibroblast properties and monocyte recruitment.
• Analysis of KDM6B gene signature in murine and human disease samples.

Main Results:

• Lysine demethylase 6B (KDM6B) induction is identified as a primary epigenetic driver of early immunofibroblast differentiation.
• KDM6B gene signature is enriched in murine inflammatory fibroblasts and pathogenic stroma from autoimmune disease patients.
• KDM6B is essential for acquiring LSC/immunofibroblast functions, including CCL2 upregulation and monocyte recruitment.

Conclusions:

• Epigenetic mechanisms, particularly KDM6B, are critical for early immunofibroblast commitment and immune functions.
• KDM6B plays a significant role in orchestrating immune cell interactions within inflammatory environments.
• Epigenetic modifiers targeting fibroblasts represent a promising therapeutic strategy for chronic inflammatory conditions.