Rhythmic U2af26 alternative splicing controls PERIOD1 stability and the circadian clock in mice.
The circadian clock drives daily rhythms in gene expression to control metabolism, behavior, and physiology; while the underlying transcriptional feedback loops are well defined, the impact of alternative splicing on circadian biology remains poorly understood. Here we describe a robust circadian and light-inducible splicing switch that changes the reading frame of the mouse mRNA encoding U2-auxiliary-factor 26 (U2AF26). This results in translation far into the 3' UTR, generating a C terminus with homology to the Drosophila clock regulator TIMELESS. This new U2AF26 variant destabilizes PERIOD1 protein, and U2AF26-deficient mice show nearly arrhythmic PERIOD1 protein levels and broad defects in circadian mRNA expression in peripheral clocks. At the behavioral level, these mice display increased phase advance adaptation following experimental jet lag. These data suggest light-induced U2af26 alternative splicing to be a buffering mechanism that limits PERIOD1 induction, thus stabilizing the circadian clock against abnormal changes in light:dark conditions.
Philipps-University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35032 Marburg, Germany.
Marco
M
Preußner
Philipps-University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35032 Marburg, Germany.
Ilka
I
Wilhelmi
Philipps-University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35032 Marburg, Germany.
Astrid-Solveig
AS
Schultz
Philipps-University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35032 Marburg, Germany.
Florian
F
Finkernagel
Philipps-University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35032 Marburg, Germany.
Monika
M
Michel
Institut de Recherches Cliniques de Montréal (IRCM), 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada.
Tarik
T
Möröy
Philipps-University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35032 Marburg, Germany. Electronic address: florian.heyd@fu-berlin.de.
Florian
F
Heyd
D017398:Alternative Splicing; D000818:Animals; D001522:Behavior, Animal / Q000528:radiation effects; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D057906:Circadian Clocks / Q000235:genetics; D002940:Circadian Rhythm; D016368:Frameshift Mutation; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D056950:Period Circadian Proteins / Q000378:metabolism*; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism*; D000072668:Splicing Factor U2AF
D018797:Cell Cycle Proteins; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C443672:U2af1l4 protein, mouse