Stress-Induced Transcriptional Memory Accelerates Promoter-Proximal Pause-Release and Decelerates Termination over Mitotic Divisions

Anniina Vihervaara; Dig Bijay Mahat; Samu V. Himanen; Malin A.H. Blom; John T. Lis; Lea Sistonen

Heat-responsiveness was restored for the vast majority of genes in preconditioned K562 cells 226! ( Figure 3B ), but a subset of genes lost, gained or accelerated heat induction due to 227! preconditioning ( Figure 3E ). One of the genes that had lost heat induction encodes Protein 228! Phosphatase 1 Regulatory subunit 15A (PPP1R15A alias GADD34; Figure 3E ) that counteracts 229! stress-induced inhibition of translation by dephosphorylating eukaryote Initiation Factor 2 alpha 230! (eIF2α; Harding et al., 2009; Walter and Ron, 2011) . In support of inhibited protein synthesis in 231! preconditioned cells, the few genes that had gained heat induction included proteins with function 232! in cell survival and growth arrest (Supplementary Dataset 1). Albeit certain genes gained 233! accelerated heat induction ( Figure 3E ), we did not detect increased Pol II density at the promoter-234! ! ! 10! proximal regions ( Figure S3F ), as was detected in MEFs ( Figure 1C ) after a 48-hour recovery 235! from stress. On the contrary, 5'-sequences of heat-induced genes gained less Pol II in 236! preconditioned K562 cells upon heat shock ( Figure 3F ). The differences in Pol II entry into heat-237! activated genes indicated either cell-type specificity, or more likely, diverging strategies to re-238! wire transcriptional responsiveness in cells that were exposed to either a single or multiple heat 239! shocks.