Role for LSM genes in the regulation of circadian rhythms

Abstract

Growing evidence suggests that core spliceosomal components differentially affect RNA processing of specific genes; however, whether changes in the levels or activities of these factors control specific signaling pathways is largely unknown. Here we show that some SM-like (LSM) genes, which encode core components of the spliceosomal U6 small nuclear ribonucleoprotein complex, regulate circadian rhythms in plants and mammals. We found that the circadian clock regulates the expression of LSM5 in Arabidopsis plants and several LSM genes in mouse suprachiasmatic nucleus. Further, mutations in LSM5 or LSM4 in Arabidopsis, or down-regulation of LSM3, LSM5, or LSM7 expression in human cells, lengthens the circadian period. Although we identified changes in the expression and alternative splicing of some core clock genes in Arabidopsis lsm5 mutants, the precise molecular mechanism causing period lengthening remains to be identified. Genome-wide expression analysis of either a weak lsm5 or a strong lsm4 mutant allele in Arabidopsis revealed larger effects on alternative splicing than on constitutive splicing. Remarkably, large splicing defects were not observed in most of the introns evaluated using RNA-seq in the strong lsm4 mutant allele used in this study. These findings support the idea that some LSM genes play both regulatory and constitutive roles in RNA processing, contributing to the fine-tuning of specific signaling pathways.posttranscriptional | alternative splicing | circadian clock | Arabidopsis | mammals C ircadian rhythms are persistent 24-h oscillations in biological processes that occur under constant environmental conditions. They allow organisms to coordinate multiple physiological processes with periodic or seasonal changes that occur in the environment. At the heart of the eukaryotic circadian system lies a complex set of interconnected transcriptional and translational feedback loops, in which a group of core clock genes regulate each other to ensure that their mRNA levels oscillate with a period of ∼24 h (1). The core oscillator in Arabidopsis thaliana involves two MYB domain-containing transcription factors, CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY), that repress the expression of TIMING OF CAB2 EXPRESSION 1 (TOC1) at the beginning of the day. In turn, TOC1, a member of the PSEUDO-RESPONSE REGULATOR (PRR) family, represses CCA1/LHY expression at the end of the day (2). Other clock components expressed throughout the day form multiple interconnected transcriptional feedback loops (2).Mounting evidence indicates that alternative splicing (AS), the process by which pre-mRNA molecules are differentially spliced to yield multiple mRNA isoforms from a single gene, plays a key role in the regulation of circadian networks in a variety of organisms, including Drosophila melanogaster (3), Neurospora crassa (4-6), and Arabidopsis (7-11). For example, the core clock genes period in Drosophila and frequency in Neurospora give rise to different mRNA isoforms through AS, which helps t...

The spliceosome assembly factor GEMIN2 attenuates the effects of temperature on alternative splicing and circadian rhythms

“…We observed that GEMIN2 had a greater effect on alternative than on constitutive splicing, a phenomenon that has already been reported for several core snRNP components, such as SmB (19), LSm4 (20), or U1C (21) (Fig. 2B).…”

“…We previously showed that PRMT5, an arginine methyltransferase that methylates Sm and LSm spliceosomal proteins, is important for the proper regulation of circadian rhythms in Arabidopsis and flies (27). Other splicing factors known to control clock function in plants are LSm4 and LSm5 (core components of the U6 snRNP) (20) and STIPL (28), an Arabidopsis protein with homology to a splicing factor involved in spliceosome disassembly in humans and yeast. In addition, the Arabidopsis homolog of the mammalian SKI interacting protein (SKIP), a splicing factor present in the spliceosomal NineTeen complex, also regulates the circadian period length in plants (29).…”

Systems Chronotherapeutics

“…Furthermore, epigenetic regulation has been found to play a role in clock regulation (Papazyan et al, 2016) and rhythmic changes in the chromatin landscape of the DNA (Koike et al, 2012) and histone and DNA modifications have been reported (Ripperger and Merrow, 2011; Sahar and Sassone-Corsi, 2013; Azzi et al, 2014), and so have splicing and RNA modification as well as ribosomal translation (McGlincy et al, 2012; Lim and Allada, 2013; Perez-Santangelo et al, 2014; Jang et al, 2015; Janich et al, 2015). …”

Ribosome profiling reveals an important role for translational control in circadian gene expression

“…The LSM1 gene showed rhythmic RPF accumulation and an expressed, albeit nonoscillatory, uORF. A recent study has implicated other LSM genes as regulators of the plant and mammalian clocks (Perez-Santangelo et al 2014). Interestingly, LSM1 encodes an RNA binding protein that is involved in mRNA metabolism and is a necessary component for the formation of processing bodies, more commonly known as P bodies, in human cells (Andrei et al 2005;Chu and Rana 2006).…”