Epigenetic reader SP140 loss of function drives Crohn's disease due to uncontrolled macrophage topoisomerases

Area of Science:

• Immunology
• Epigenetics
• Molecular Biology

Background:

• Speckled Protein 140 (SP140) is an epigenetic regulator implicated in immune disorders like Crohn's disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL).
• The precise mechanisms by which SP140 mutations contribute to disease pathogenesis remain largely unknown.

Purpose of the Study:

• To elucidate the molecular function of SP140 in immune regulation.
• To investigate the role of SP140 in maintaining chromatin structure and macrophage function.
• To explore therapeutic strategies targeting SP140-associated immune defects.

Main Methods:

• Global proteomic analysis to identify SP140 interacting proteins.
• In vitro and in vivo studies using SP140 loss-of-function models (SP140-/- mice).
• Assessment of macrophage transcriptional programs, bacterial killing assays, and pharmacological inhibition of topoisomerases (TOP1/2).

Main Results:

• SP140 was identified as a repressor of topoisomerases (TOPs), crucial for maintaining heterochromatin and macrophage identity.
• SP140 deficiency led to increased TOP activity, aberrant gene expression, and impaired macrophage responses to microbes.
• Pharmacological inhibition of TOP1/2 restored normal macrophage function and ameliorated intestinal pathology in SP140-deficient mice.
• TOP1/2 inhibition specifically rescued defects in SP140-/- mice, not wild-type mice.

Conclusions:

• SP140 acts as a critical repressor of topoisomerases, safeguarding epigenetic stability and immune cell function.
• Loss of SP140 function unleashes TOP activity, causing de-repression of silenced genes and immune dysfunction.
• Targeting topoisomerase activity represents a promising therapeutic approach for immune diseases associated with SP140 loss.