Tina Dahlby - The role of CBP and EZH2 as molecular switches of the ER stress response in pancreatic cells

Type 2 diabetes (T2DM) is caused by relative insulin deficiency arising when pancreatic β-cell insulin secretion fails to compensate for insulin resistance. Elevated blood free fatty acids and after T2DM onset glucose are mediators of β-cell failure in T2DM.

Posttranslational modifications by acetylation and methylation of the histone backbone in chromatin are important epigenetic modulators of gene transcription. We previously showed that inhibition of histone deacetylases (HDAC) prevents both inflammatory and glucolipotoxicity (GLT) induced β-cell apoptosis, associated with hyperacetylation of the transcription factor NFκB preventing transcriptional activation of inflammatory gene promoters, and with alleviation of endoplasmic reticulum (ER) and mitochondrial stress, respectively.

The precise targets in the ER pathway, however, are unknown. By unbiased analyses of the acetylome by mass spectrometry (MS) or the gene expression profile by microarray of insulin-producing cells exposed to GLT in the presence or absence of HDAC inhibitors (HDACi) we identified cAMP response element-binding transcription factor (CREB) binding protein (CBP) and Enhancer of zeste homolog 2 (EZH2) as key target candidates.

Preliminary data show that GLT activates CBP, that this activation is prevented by HDAC inhibition, and that shRNA mediated knockdown of EZH2 protects against GLT induced β-cell apoptosis. Here we propose to investigate the role of CBP and EZH2 as transcriptional co-activators of NFκB, thereby acting as molecular switches of ER stress from a protective to a proapoptotic response. The perspective of this proposal is to reveal novel therapeutic strategies for T2DM by targeting CBP and/or EZH2.