Body Temperature Cycles Control Rhythmic Alternative Splicing in Mammals

Mol Cell. 2017 Aug 3;67(3):433-446.e4. doi: 10.1016/j.molcel.2017.06.006. Epub 2017 Jul 6.


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.

Keywords: SR proteins; Tbp; U2af; alternative splicing; body temperature; circadian clock; molecular thermometer; phosphorylation; splicing network.

MeSH terms

  • 5' Untranslated Regions
  • Alternative Splicing*
  • Animals
  • Body Temperature Regulation*
  • Cell Line, Tumor
  • Circadian Clocks*
  • Circadian Rhythm*
  • Exons
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • Phosphorylation
  • RNA Interference
  • Serine-Arginine Splicing Factors / genetics
  • Serine-Arginine Splicing Factors / metabolism
  • Splicing Factor U2AF / genetics
  • Splicing Factor U2AF / metabolism
  • TATA-Box Binding Protein / genetics
  • TATA-Box Binding Protein / metabolism*
  • Time Factors
  • Transfection


  • 5' Untranslated Regions
  • SRSF2 protein, mouse
  • Splicing Factor U2AF
  • TATA-Box Binding Protein
  • U2af1l4 protein, mouse
  • Serine-Arginine Splicing Factors