Body Temperature Cycles Control Rhythmic Alternative Splicing in Mammals

Abstract

The core body temperature of all mammals oscillates with the time of the day. However, direct molecular consequences of small, physiological changes in body temperature remain largely elusive. Here we show that body temperature cycles drive rhythmic SR protein phosphorylation to control an alternative splicing (AS) program. A temperature change of 1°C is sufficient to induce a concerted splicing switch in a large group of functionally related genes, rendering this splicing-based thermometer much more sensitive than previously described temperature-sensing mechanisms. AS of two exons in the 5' UTR of the TATA-box binding protein (Tbp) highlights the general impact of this mechanism, as it results in rhythmic TBP protein levels with implications for global gene expression in vivo. Together our data establish body temperature-driven AS as a core clock-independent oscillator in mammalian peripheral clocks.

Lnc RNA ‐dependent nuclear stress bodies promote intron retention through SR protein phosphorylation

“…The RS domain is required for protein-protein interactions with other SRSFs or RS domain-harboring proteins (Xiao & Manley, 1997). Notably, the phosphorylation state of the RS domain is dynamically changed in response to environmental transitions, such as thermal stress or circadian changes in body temperature (Guil & Caceres, 2007;Preussner et al, 2017). Notably, the phosphorylation state of the RS domain is dynamically changed in response to environmental transitions, such as thermal stress or circadian changes in body temperature (Guil & Caceres, 2007;Preussner et al, 2017).…”

Temperature‐controlled Rhythmic Gene Expression in Endothermic Mammals: All Diurnal Rhythms are Equal, but Some are Circadian

“…At first glance, this feature appears less important in endothermic organisms with a rather stable body temperature such as mammals (see Figure ), as changes in the ambient temperature are compensated at the organismic level (in endothermic organism changes in the ambient temperature are not strongly reflected in body temperature changes). However, mammals show circadian rhythms in body temperature and we have identified many body temperature‐controlled alternative splicing rhythms, which, depending on the model system used, react to changes in ambient temperature or not . The conflict of temperature‐compensation and temperature as an entrainment factor will be further discussed below.…”

“…Through our recent characterization of temperature‐regulated alternative splicing, we have gained first mechanistic insights into such a core‐clock independent rhythm (Figure A). These rhythms use cycles in body temperature as a Zeitgeber to generate rhythms in alternative splicing of several hundred genes, but are unresponsive to the phase of the peripheral clock . But what are the molecular components that allow temperature‐sensing to generate rhythms in alternative splicing?…”

The heat's on: nuclear stress bodies signal intron retention

“…While a full HS response might occur only during episodes of high fever in mammals, it is interesting to note that the normal mammalian body temperature oscillates with the time of the day, which drives rhythmic phosphorylation of SR proteins together with concerted changes in splicing (Preußner et al, 2017). While a full HS response might occur only during episodes of high fever in mammals, it is interesting to note that the normal mammalian body temperature oscillates with the time of the day, which drives rhythmic phosphorylation of SR proteins together with concerted changes in splicing (Preußner et al, 2017).…”