Atherosclerosis ·30 Oct 2026 ·Added 10 Nov 2026

Myeloid deficiency of the PRC2 complex protein JARID2 promotes foam cell formation through elevated plasma lipids without altering atherosclerosis progression.

Lobke F Zijlstra, Maartje M C Hof, Lisa Willemsen, Marie A C Depuydt, Cindy P A A van Roomen, Marion J J Gijbels, Guillermo R Griffith, Ingeborg van der Made, Myrthe den Toom, Koen H M Prange, Johannes H M Levels, Judith C Sluimer, Menno P J de Winther, Annette E Neele

Biochemistry

DOI ↗

Abstract

Atherosclerosis is a chronic inflammatory disease in which macrophages drive plaque development, progression, and eventual destabilization. Epigenetic modulation of macrophages may offer a promising approach to reduce disease progression and residual inflammatory risk that persists despite lipid-lowering therapy. EZH2, the catalytic subunit of PRC2 responsible for depositing H3K27me3, a histone modification associated with gene silencing, is pro-atherogenic in macrophages, while the contribution of PRC2 co-factors remains unexplored. We found the co-factor Jumonji AT-Rich Interactive Domain 2 (JARID2) to be upregulated in unstable human atherosclerotic plaques, prompting us to investigate its role in atherosclerosis. To investigate the role of macrophage Jarid2 in atherosclerosis, we generated myeloid-specific Jarid2-deficient mice (Jarid2del; LysMCreJarid2fl/fl). Bone marrow from Jarid2del or control (Jarid2wt) mice was transplanted to Ldlr-/- recipients, followed by a high cholesterol diet for 9 weeks to induce atherosclerosis. Myeloid Jarid2 deficiency modestly increased plasma cholesterol and triglyceride levels and enhanced foam cell formation. Despite increased plasma lipid levels, atherosclerotic lesion size and composition remained unchanged. Single-cell RNA sequencing of aortic arch plaques revealed that Jarid2 deficiency has both pro- and anti-inflammatory effects in multiple myeloid subsets. Together, the elevated plasma lipid levels and mixed context-dependent inflammatory phenotype suggest that opposing, potentially compensatory mechanisms counterbalance each other, resulting in no net change in overall plaque size. JARID2 is upregulated in unstable human atherosclerotic plaques, whereas myeloid Jarid2 deficiency in mice modestly elevates plasma lipid levels and promotes foam cell formation without affecting atherosclerosis progression.