Alternative splicing coupled mRNA decay shapes the temperature‐dependent transcriptome

Abstract

Mammalian body temperature oscillates with the time of the day and is altered in diverse pathological conditions. We recently identified a body temperature‐sensitive thermometer‐like kinase, which alters SR protein phosphorylation and thereby globally controls alternative splicing (AS). AS can generate unproductive variants which are recognized and degraded by diverse mRNA decay pathways—including nonsense‐mediated decay (NMD). Here we show extensive coupling of body temperature‐controlled AS to mRNA decay, leading to global control of temperature‐dependent gene expression (GE). Temperature‐controlled, decay‐inducing splicing events are evolutionarily conserved and pervasively found within RNA‐binding proteins, including most SR proteins. AS‐coupled poison exon inclusion is essential for rhythmic GE of SR proteins and has a global role in establishing temperature‐dependent rhythmic GE profiles, both in mammals under circadian body temperature cycles and in plants in response to ambient temperature changes. Together, these data identify body temperature‐driven AS‐coupled mRNA decay as an evolutionary ancient, core clock‐independent mechanism to generate rhythmic GE.

SRSF10: an atypical splicing regulator with critical roles in stress response, organ development, and viral replication

“…This striking temperature-driven alternative splicing control of mRNA decay has been observed for many RBPs and constitutes an important layer of rhythmic gene expression (Neumann et al 2020).…”

“…While this PTC may trigger NMD on transcripts that have also undergone exons 3/4 splicing, transcripts made by use of the alternative polyadenylation site in exon 3 (Fig. 1b) appear less affected (Neumann et al 2020). Notably, relative to 34˚C, E2a/E3 splicing decreases at 38˚C in both mouse hepatocytes and human HEK293 cells, possibly indicating decreased phosphorylation of SRSF10 by the temperature-dependent CLK kinases (Haltenhof et al 2020).…”

Layers of crosstalk between circadian regulation and environmental signalling in plants

“…Alternative splicing is a pervasive co-transcriptional mechanism that regulates the transcriptome and proteome by generating multiple forms of mature transcripts from the same precursor mRNAs (pre-mRNAs) 66,67 . In mammals 68 and plants 69 there is evidence that alternative splicing responds to environmental cues such as light 70 and temperature 69 to alter gene expression (Figure 1A). An example of light-regulated alternative splicing in Arabidopsis involves a light-regulated signal from the chloroplast to nucleus 71 .…”

Roles of peripheral clocks: lessons from the fly

“…In mammals, body temperature cycles can generate rhythmic gene expression in the periphery independent of peripheral clocks; for instance, temperature cycles, but not the clock, control the rhythmic expression of cold-induced RNA binding protein, which imparts robustness to peripheral clocks by enhancing Clock mRNA accumulation [102]. Rhythmic changes in body temperature shape global gene expression in the periphery through alternative splicing coupled RNA decay [103]. Temperature differences are sensed by CDC-like kinases (CLK), which then phosphorylate and alter the activity of some of SR proteins, subsequently controlling the global alternative splicing [104].…”