Mammalian TOR as a central modulator of the transcriptional response of keratinocyte stem cells to small temperature variations

Abstract

Being in the layer at the interface of the body with the outside world, keratinocyte stem cells constantly adapt and respond to environmental cues such as temperature and oxygen. However, until now, experiments involving temperature have only examined cold and heat shocks. Here, our work illustrates that small variations of temperature ( 1°C) are enough to affect colony size of keratinocyte stem cells and alter expression of some genes involved in various signalling pathways. The promoter regions of the temperature sensitive genes share a sequence located in some Alu short interspersed nuclear elements (Alu SINEs). This sequence termed TORRID contains several IFHL-like motifs (IFHL motif is related to ribogenesis in yeast) and interestingly a minimal TORRID sequence might be enough for a gene to acquire temperature sensitivity. Our findings demonstrated that the expression of temperature sensitive genes is regulated through the mammalian target of rapamycin (mTOR) pathway. The transcription factors ILF1 and RAP1, and histone deacetylase II (HDAC2) –human orthologs of yeast Fhl1p, Rap1 and Rpd3 respectively– associate with TORRID sequences. Small variations of temperature were enough to alter this association. Moreover, mTOR can translocate to the nucleus and associate with the TORRID sequences in a rapamycin and temperature dependent manner. Furthermore, Raptor and Rictor, members of the mTOR complexes 1 and 2 are also involved in this binding. Hence, our results reveal not only that TOR transcriptional activity is evolutionary conserved from yeast to human, but also that a small variation in temperature represents a new input to the mTOR pathway and fine-tune regulation of transcription through TORRID sequences. These results shed new light on the role of Alus in gene regulation.