A Conserved Kinase-Based Body Temperature Sensor Globally Controls Alternative Splicing and Gene Expression

Haltenhof, Tom; Kotte, Ana; Bortoli, Francesca De; Schiefer, Samira; Meinke, Stefan; Emmerichs, Ann-Kathrin; Petermann, Kristina Katrin; Timmermann, Bernd; Franz, Andreas; Wahl, Markus; Imhof, Petra; Preußner, Marco

doi:10.2139/ssrn.3486026

Cited by 12 publications

(21 citation statements)

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“…In the presented examples, a temperature change of 4°C is sufficient to change AS by 20–30%, e.g., Hnrnpdl from 60 to 95%, indicating a strong regulatory impact on the expression of the respective RBPs (Fig 2A). We have recently shown this particular temperature‐dependent AS event in Cirbp to be regulated by CLK activity and found that E7b inclusion reduces Cirbp GE (Haltenhof et al , 2020). In line with these findings, we find the E7b isoform to be strongly stabilized by CHX and observe a correlation of higher abundance of the poison isoforms (particularly in the CHX condition) with decreased overall GE in the DMSO control in Cirbp and all other cases analyzed (Fig 2B).…”

Section: Resultsmentioning

confidence: 96%

“…An SR protein that is inactive due to its phosphorylation level results in the accumulation of its mRNA and (inactive) protein. Upon a switch to the activating body temperature, phosphorylation of the SR protein changes through altered CLK activity (Haltenhof et al , 2020) and the activated SR proteins promotes poison exon inclusion within their own pre‐mRNA. Degradation of the unproductive mRNA isoform then leads to low but active protein levels.…”

Section: Discussionmentioning

confidence: 99%

“…In mammals, this network requires sensors and modulators that are sensitive enough to respond to temperature differentials of around 1°C, to be able to respond to daily changes in body temperature. In recent work, we have characterized CLK kinases as the direct molecular sensor of such temperature changes (Haltenhof et al , 2020). Interestingly, we find in evolutionary distant species that groups of SR proteins are antagonistically affected by temperature, such that one group is activated by hyperphosphorylation, whereas this leads to inactivation of another group of SR proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Here, exon inclusion results in an interrupted or non-functional GFP variant while exon skipping results in functional GFP (Figs 2D and EV2B). Both an exon encoding a stop codon from Ythdf3 and an exon that interrupts the GFP-coding frame from human Synerg (Haltenhof et al, 2020) show exon inclusion almost exclusively in cold (Fig 2E). In both examples, exon skipping in warm clearly correlates with higher GFP expression ( Fig 2F).…”

Section: Rbp Expression Is Controlled Through Temperature-dependent Amentioning

confidence: 99%

“…Essential regulators are members of the family of SR proteins (13 canonical members in human), which share a domain rich in serine and arginine residues, known as the RS domain (Manley & Krainer, 2010). The phosphorylation level of SR proteins controls their activity and serves as a fast and extremely sensitive molecular thermometer transferring the signal “body temperature” into global changes in AS (Haltenhof et al , 2020). SR proteins contain ultraconserved elements, allowing autoregulation of their own expression level (Lareau et al , 2007).…”

Section: Introductionmentioning

confidence: 99%

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Alternative splicing coupled mRNA decay shapes the temperature‐dependent transcriptome

et al. 2020

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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.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Rbp Expression Is Controlled Through Temperature-dependent Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alternative splicing coupled mRNA decay shapes the temperature‐dependent transcriptome

et al. 2020

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Nanothermometry for cellular temperature monitoring and disease diagnostics

Liu,

Sun,

Teh

et al. 2024

Interdisciplinary Medicine

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Body temperature variations, including the generation, transfer, and dissipation of heat, play an important role throughout life and participate in all biological events. Cellular temperature information is an indispensable link in the comprehensive understanding of life science processes, but traditional testing strategies cannot provide sufficient information due to their low precision and inefficient cellular‐entrance. In recent years, with the help of luminescent nanomaterials, a variety of new thermometers have been developed to achieve real‐time temperature measurement at the micro/nano scale. In this review, we summarized the latest advances in several nanoparticles for cellular temperature detection and their related applications in revealing cell metabolism and disease diagnosis. Furthermore, this review proposed a few challenges for the nano‐thermometry, expecting to spark novel thought to push forward its preclinical and translational uses.

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Sex determination without sex chromosomes

Weber

Capel

2021

Phil. Trans. R. Soc. B

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With or without sex chromosomes, sex determination is a synthesis of many molecular events that drives a community of cells towards a coordinated tissue fate. In this review, we will consider how a sex determination pathway can be engaged and stabilized without an inherited genetic determinant. In many reptilian species, no sex chromosomes have been identified, yet a conserved network of gene expression is initiated. Recent studies propose that epigenetic regulation mediates the effects of temperature on these genes through dynamic post-transcriptional, post-translational and metabolic pathways. It is likely that there is no singular regulator of sex determination, but rather an accumulation of molecular events that shift the scales towards one fate over another until a threshold is reached sufficient to maintain and stabilize one pathway and repress the alternative pathway. Investigations into the mechanism underlying sex determination without sex chromosomes should focus on cellular processes that are frequently activated by multiple stimuli or can synthesize multiple inputs and drive a coordinated response. This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’.

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A Conserved Kinase-Based Body Temperature Sensor Globally Controls Alternative Splicing and Gene Expression

Cited by 12 publications

References 12 publications

Alternative splicing coupled mRNA decay shapes the temperature‐dependent transcriptome

Alternative splicing coupled mRNA decay shapes the temperature‐dependent transcriptome

Nanothermometry for cellular temperature monitoring and disease diagnostics

Sex determination without sex chromosomes

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