Lellahi SM, Rosenlund IA, Hedberg A, Kiær LT, Mikkola I, Knutsen E, Perander M
The long non-coding RNA (lncRNA) NEAT1 is the architectural component of nuclear paraspeckles, and has recently gained considerable attention as it is abnormally expressed in pathological conditions such as cancer and neurodegenerative diseases. NEAT1 and paraspeckle formation are increased in cells upon exposure to a variety of environmental stressors, and believed to play an important role in cell survival. The present study was undertaken to further investigate the role of NEAT1 in cellular stress response pathways. We show that NEAT1 is a novel target gene of heat shock transcription factor 1 (HSF1), and upregulated when the heat shock response pathway is activated by Sulforaphane (SFN) or elevated temperature. HSF1 binds specifically to a newly identified conserved heat shock element (HSE) in the NEAT1 promoter. In line with this, SFN induced the formation of NEAT1-containing paraspeckles via a HSF1-dependent mechanism. HSF1 plays a key role in the cellular response to proteotoxic stress by promoting the expression of a series of genes, including those encoding molecular chaperones. We have found that the expression of HSP70, HSP90, and HSP27 is amplified and sustained during heat shock in NEAT1-depleted cells compared to control cells, indicating that NEAT1 feeds back via an unknown mechanism to regulate HSF1 activity. This interrelationship is potentially significant in human diseases such as cancer and neurodegenerative disorders.