The activation of monocytes and macrophages plays a central role in chronic inflammation associated with type 2 diabetes mellitus (T2D) and cardiovascular disease. However, the precise epigenetic mechanisms involved are unclear. From RNA-seq analysis we found dysregulated expression of several genes, including downregulation of JARID2 in human CD14+ monocytes obtained from T2D patients versus controls. JARID2 protein functions as a transcription repressor by facilitating the recruitment of polycomb repressor complex 2 and associated histone H3K27-trimethylation to target genes. RT-qPCR and RNA-seq analysis showed that high glucose +TNF-α (HT) , key pathological factors in diabetes, downregulated JARID2 in human monocytes along with genes involved in inflammation and cytokine related signaling networks. Western blotting also showed HT reduces JARID2 protein levels in human monocytes. Furthermore, JARID2 knockdown with siRNAs increased proliferation and enhanced LPS and HT induced inflammatory genes in human monocytes. ATAC-seq revealed that HT increased chromatin-accessibility at promoters of inflammatory genes like IL1B that were upregulated by JARID2 knockdown. Interestingly, microRNA-seq analysis revealed that CD14+ monocytes from T2D patients showed increased expression of several microRNAs with complementarity to the JARID2 3’-UTR, indicating cross-talk between epigenetic factors and microRNA-dependent mechanisms. Mouse orthologous Jarid2 was downregulated in macrophages from diabetic db/db mice and in macrophages from normal C57BL/6 mice treated with HT, similar to human JARID2. These results demonstrate that JARID2 plays a key role in chromatin remodeling and restraining inflammatory genes in monocytes, and its downregulation in T2D can augment inflammation. Further, understanding of epigenetic regulators like JARID2 can lead to novel therapies for chronic inflammatory diabetic complications.

Disclosure

M.A.Reddy: None. V.S.Tanwar: None. L.Zhang: None. L.L.Lanting: None. M.Wang: None. P.Pandey: None. Z.Chen: None. X.Wu: None. R.Natarajan: None.

Funding

National Institutes of Health (DK065073) to RN AR-DMRI Endowment Pilot grant to MAR

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