The TrxG Complex Mediates Cytokine Induced De Novo Enhancer Formation in Islets: e0141470

• Published in: PloS one Vol. 10; no. 10
• Main Authors: Tennant, Bryan R, Hurley, Peter, Dhillon, Jasmine, Gill, Amol, Whiting, Cheryl, Hoffman, Brad G
• Format: Journal Article
• Language: English
• Published: 01.10.2015
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0141470

To better understand how [Beta]-cells respond to proinflammatory cytokines we mapped the locations of histone 3 lysine 4 monomethylation (H3K4me1), a post-translational histone modification enriched at active and poised cis-regulatory regions, in IFN[gamma], Il-1[Beta], and TNF[alpha] treated pancreatic islets. We identified 96,721 putative cis-regulatory loci, of which 3,590 were generated de novo, 3,204 had increased H3K4me1, and 5,354 had decreased H3K4me1 in IFN[gamma], Il-1[Beta], and TNF[alpha] exposed islets. Roughly 10% of the de novo and increased regions were enriched for the repressive histone modification histone 3 lysine 27 trimethylation (H3K27me3) in untreated cells, and these were frequently associated with chemokine genes. We show that IFN[gamma], Il-1[Beta], and TNF[alpha] exposure overcomes this repression and induces chemokine gene activation in as little as three hours, and that this expression persists for days in absence of continued IFN[gamma], Il-1[Beta], and TNF[alpha] exposure. We implicate trithorax group (TrxG) complexes as likely players in the conversion of these repressed loci to an active state. To block the activity of these complexes, we suppressed Wdr5, a core component of the TrxG complexes, and used the H3K27me3 demethylase inhibitor GSK-J4. We show that GSK-J4 is particularly effective in blunting IFN[gamma], Il-1[Beta], and TNF[alpha] -induced chemokine gene expression in [Beta]-cells; however, it induced significant islet-cell apoptosis and [Beta]-cell dysfunction. Wdr5 suppression also reduced IFN[gamma], Il-1[Beta], and TNF[alpha] induced chemokine gene expression in [Beta]-cells without affecting islet-cell survival or [Beta]-cell function after 48hrs, but did begin to increase islet-cell apoptosis and [Beta]-cell dysfunction after four days of treatment. Taken together these data suggest that the TrxG complex is potentially a viable target for preventing cytokine induced chemokine gene expression in [Beta]-cells.