Set4 Promotes Survival during Oxidative Stress through Regulation of Stress Response Genes

Abstract

The yeast protein Set4 contains both a PHD finger and a SET domain, a common signature of chromatin regulatory proteins, and shares sequence homology with the yeast protein Set3, the fly protein UpSET and the human protein MLL5. Although MLL5 has been implicated in diverse pathways such as hematopoiesis and spermatogenesis, as well as disease states including neurodevelopmental disorders and cancer, its cellular function is still largely unclear. The biological role for Set4 and its function in chromatin regulation has not been investigated. Set4 had previously been reported to be lowly expressed under normal growth conditions, and therefore not expected to have a substantial role in chromatin function or gene expression regulation. However, our data indicated that it plays a highly‐specialized role during stress responses, and that it is a key context‐dependent chromatin regulator. Specifically, we have determined that Set4 activity is critically‐balanced in the cell to promote survival specifically during oxidative stress. Gene expression analysis indicates that the role for Set4 during oxidative stress is to activate genes that promote survival in the presence of oxidative insults. Our data further indicate that Set4 interacts with chromatin in a highly‐regulated manner, and it directly associates with stress‐response genes upon oxidative damage. Our results suggest a model in which Set4 is a stress‐responsive chromatin protein that promotes the activation of gene expression programs required for cellular protection during oxidative stress. To our knowledge, this work is the first to define a biological role for Set4, a conserved SET‐domain protein in yeast that was predicted, although not yet characterized, to be a chromatin regulator. These results further our understanding of mechanisms that protect cells during oxidative stress, and will open new avenues for the investigation of the Set3‐Set4 subfamily of SET‐domain containing proteins and their roles in gene expression control in response to fluctuating environmental conditions.Support or Funding InformationNIH R01GM124342This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.