Dynamics of histone modifications at the cytokine-inducible promoters for IDO1 and TSG-6 in human bone-marrow derived MSCs

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	FDA/CBER	STEMCELL-3

Authors

• P.J. Lynch
• Y.I. Rovira Gonzalez
• H.A. Hursh

Abstract

Bone marrow-derived multipotent stromal cells (BM-MSCs) are attractive candidates for cell-based therapies due to their capacity to modulate immune system cells. Here, we investigated whether chromatin structures contribute to regulating immunomodulatory gene expression in human BM-MSCs. We assayed the transcriptionally permissive and repressive histones surrounding the promoters for IDO1 and TSG-6, which were selected for their roles in immunomodulation and sensitivity to pro-inflammatory cytokines. The IDO1 promoter was enriched by repressive H3K9me3 in resting BM-MSCs. Twenty-four hour treatment with the cytokines INF-γ and TNF-α resulted in demethylation of H3K9 concomitant with a gain in acetylation of the same residue and activation of IDO1 mRNA. Residual levels of H3K9me3 were still observed above background in one donor of BM-MSCs following exposure to cytokines. Cytokine-treatment of fibroblasts for the same amount of time resulted in complete removal of H3K9me3 from IDO1. Similar to IDO1, gene expression of TSG-6 was up-regulated during treatment. In contrast to IDO1, we observed no H3K9me3 enrichment at TSG-6. Acetylated H3K9 associated with TSG-6 at similar levels before and after cytokine treatment. Our results demonstrate that activation of IDO1, but not TSG-6, is regulated in part through heterochromatin structures that are removed upon exposure to pro-inflammatory cytokines.

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