Cells experience various proteotoxic stress, which causes severe damages unless managed by cellular stress responses. These include the heat shock response, hypoxic stress response, osmotic stress response, unfolded protein response, and oxidative stress response. A key regulator of cellular stress responses is the transcription factor family called heat shock factors (HSFs). One of the main interests in our laboratory is to understand the functions of HSF1 and HSF2 in response to distinct proteotoxic stresses, including oxidative stress, proteasome inhibition and repeated heat stress. We believe that depending on a cellular state, HSF1 and HSF2 can have various functions beyond the conventional heat shock response, which involves the inducible expression of heat shock proteins (Hsps). This idea is supported by many genome-wide screens performed by us and others, revealing that both HSF1 and HSF2 localize to promoters and other regulatory regions of several genes unrelated to chaperone machinery and protein folding. In order to uncover the functional impact of HSFs in different biological contexts, we utilize high-throughput methods such as ChIP-seq, PRO-seq, and RNA-seq (for details, see Methods).
Cellular Stress Responses. To maintain their function in the events of stress, cells activate specific transcriptional programs. Exposure to protein damaging stresses, such as elevated temperatures, ethanol, heavy metals, and microbial infections, activate the Heat Shock Response. When the cell encounters insufficient O2 availability, the Hypoxic Stress Response is activated. The influx of water from (hyperosmotic stress) or into (hypoosmotic stress) the cell, results in mounting the Osmotic Stress Response. Protein misfolding in specific organelles activates the Unfolded Protein Response (UPR), either in mitochondria (UPRmt) or endoplasmatic reticulum (UPRER). Uncontrolled increase in reactive oxygen species (ROS) turns on the Oxidative Stress Response.
HSFs drive transcription of distinct genes and enhancers during oxidative stress and heat shock.
Himanen SV, Puustinen MC, Da Silva AJ, Vihervaara A, Sistonen L.
Nucleic Acids Res. 2022 Jun 10:gkac493. doi: 10.1093/nar/gkac493. Online ahead of print.
Stress-induced transcriptional memory accelerates promoter-proximal pause release and decelerates termination over mitotic divisions.
Vihervaara A, Mahat DB, Himanen SV, Blom MAH, Lis JT, Sistonen L.
Mol Cell. 2021 Mar 22;S1097-2765(21)00175-1. doi: 10.1016/j.molcel.2021.03.007.
New insights into transcriptional reprogramming during cellular stress.
Himanen SL, Sistonen L.
J. Cell Science. 2019 132, cs238402. doi:10.1242/jcs.238402