Journal of Clinical Epigenetics Open Access

Lysine methylation signaling at chromatin

2^nd International Congress on Epigenetics & Chromatin

November 06-08, 2017 | Frankfurt, Germany

Dan Levy

Ben-Gurion University, Israel

Scientific Tracks Abstracts: J Clin Epigenet

Abstract:

Greater than fifty methyltransferases (PKMTs) are predicted to be present in the human proteome; however, the catalytic activity and substrate specificity for the majority of these enzymes is unknown. We uncovered a novel interaction between the PKMT SETD6 and the oxidative stress sensor DJ1, a protein required for Nrf2-dependent transcription of antioxidant target genes. We show that SETD6 binds DJ1 both in-vitro and in cells but does not methylate DJ1. Under basal conditions, SETD6 and DJ1 are associated with chromatin which leads to the repression of Nrf2-dependent transcription. In response to oxidative stress, SETD6 protein level at chromatin is reduced, leading to an elevation in Nrf2 expression level and to a weaker interaction between SETD6 and DJ1 at chromatin. Using the protoarray system, we have identified PAK4 as a new substrate for methylation by SETD6. Our data demonstrate that SETD6 methylates PAK4 both in vitro and at chromatin in cells. Interestingly, depletion of SETD6 in various cellular systems significantly hinders the activation of the Wnt/beta-catenin target genes. PAK4 was recently shown to regulate beta-catenin signaling, and we show that SETD6 is a key mediator of this pathway. In the presence of SETD6, the physical interaction between PAK4 and beta-catenin is dramatically increased, leading to a significant increase in the transcription of beta-catenin target genes. Taken together, these findings provide new insight into the SETD6 biology and demonstrate that SETD6 serves as a negative or a positive regulator of transcriptional signaling at chromatin through physical and catalytically dependent and independent manners. Recent Publications 1. Levy D et al. (2011) Lysine methylation of the NF-�?ºB subunit RelA by SETD6 couplesâ�?�? activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-�?ºB signaling. Nature Immunology 12(1):29-36. 2. Duchin S et al. (2015) A one step continuous kinetic assay for protein and DNA methyltransferase enzymatic activities; Epigenetics & Chromatin 8:56 3. Chen et al. (2016) SETD6 is a negative regulator of oxidative stress response 2016, BBA Gene Regulatory Mechanisms 859(2):420-7. 4. Vershinin et al. PAK4 methylation by SETD6 promotes the activation of the Wnt/�?²-catenin pathway. Journal of Biological Chemistry 291(13):6786-95. 5. Cohn O et al. (2016) Chromatin associated SETD3 negatively regulates VEGF expression. Scientific Reports 6:37115.

Biography :

Dan Levy is the Head of the lysine methylation and epigenetics signaling lab in Ben-Gurion University in Israel. The goal of his/her research is based on the hypothesis that dynamic methylation of histone and non-histone proteins at chromatin plays a key role in the regulation cellular signal transduction pathways with fundamental effect on human health. His/her aim is to identify new methylation events and to explore how these marks are generated and under which specific physiological conditions; to investigate how these marks are sensed by other cellular factors; to elucidate the molecular mechanisms that transduce these signals; how these methylation events affect gene expression programs; what the clinical relevance of these events are; and how this knowledge can be translated into therapeutic applications in the future.