Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression

Annayev, Yunus; Adar, Sheera; Chiou, Yi Ying; Lieb, Jason D.; Sancar, Aziz; Ye, Rui

doi:10.1074/jbc.m113.534651

Cited by 58 publications

(58 citation statements)

References 36 publications

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“…S2). The mouse ortholog of this gene, Gm129, has been recently identified as having a circadian pattern of expression in mice (28,29). Many of these genes display circadian expression patterns in peripheral tissues of the mouse, such as the liver, heart, and/or skeletal muscle, and in the brain, including the SCN and cerebellum.…”

Section: Resultsmentioning

confidence: 99%

“…Another example is C1ORF51 (also known as Gm129, CHRONO, and CIART). Annayev et al (29) recently found that this protein acts as a novel transcriptional repressor with highamplitude oscillations in the mouse liver that directly interacts with BMAL1 to repress CLOCK/BMAL1 function in this tissue. Here, we find that this transcript has the highest level of rhythmicity of any gene that we identified in human cortex, suggesting it may have a similar important circadian function in human brain.…”

Section: Discussionmentioning

confidence: 99%

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Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Chen

Logan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

226

219

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With aging, significant changes in circadian rhythms occur, including a shift in phase toward a “morning” chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann’s area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Chen

Logan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

226

219

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“…Quantitation of Nr1d1 and Dbp mRNA levels was performed with the primer sets as described (Annayev et al 2014). Each sample was analyzed in triplicate, and cycle thresholds of individual genes were first normalized to corresponding Gapdh mRNA expression values obtained with the primer set.…”

Section: Quantitative Real-time Pcr and Data Analysismentioning

confidence: 99%

“…Quantitation of ChIP was performed with the primer sets described previously (Annayev et al 2014). Each sample was analyzed in triplicate.…”

Section: Quantitative Real-time Pcr and Data Analysismentioning

confidence: 99%

Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock

et al. 2014

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The mammalian circadian clock is based on a transcription-translation feedback loop (TTFL) in which CLOCK and BMAL1 proteins act as transcriptional activators of Cryptochrome and Period genes, which encode proteins that repress CLOCK-BMAL1 with a periodicity of~24 h. In this model, the mechanistic roles of CRY and PER are unclear. Here, we used a controlled targeting system to introduce CRY1 or PER2 into the nuclei of mouse cells with defined circadian genotypes to characterize the functions of CRY and PER. Our data show that CRY is the primary repressor in the TTFL: It binds to CLOCK-BMAL1 at the promoter and inhibits CLOCK-BMAL1-dependent transcription without dissociating the complex (''blocking''-type repression). PER alone has no effect on CLOCK-BMAL1-activated transcription. However, in the presence of CRY, nuclear entry of PER inhibits transcription by displacing CLOCK-BMAL1 from the promoter (''displacement''-type repression). In light of these findings, we propose a new model for the mammalian circadian clock in which the negative arm of the TTFL proceeds by two different mechanisms during the circadian cycle.

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“…S1g in the supplemental material). Moreover, we examined if the promoters of these genes are bound by core clock factors identified in different chromatin immunoprecipitation sequencing (ChIP-seq) studies performed with liver cells or macrophages (8,9,(62)(63)(64)(65)(66)(67). Strikingly, 225 of these genes have been determined to be bound by at least one core clock factor (Clock, Per1, Per2, Cry1, Cry2, Npas2, Bmal1, Nr1d1, Nr1d2, or Rora; 97.8%, 1.36-fold increase above background; P Ͻ 0.001) (see Fig.…”

Section: Identification Of Genes With Circadian Expression In Nih 3t3mentioning

confidence: 99%

Identifying Novel Transcriptional Regulators with Circadian Expression

Schick

Becker

Thakurela

et al. 2016

Molecular and Cellular Biology

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Organisms adapt their physiology and behavior to the 24-h day-night cycle to which they are exposed. On a cellular level, this is regulated by intrinsic transcriptional-translational feedback loops that are important for maintaining the circadian rhythm. These loops are organized by members of the core clock network, which further regulate transcription of downstream genes, resulting in their circadian expression. Despite progress in understanding circadian gene expression, only a few players involved in circadian transcriptional regulation, including transcription factors, epigenetic regulators, and long noncoding RNAs, are known. Aiming to discover such genes, we performed a high-coverage transcriptome analysis of a circadian time course in murine fibroblast cells. In combination with a newly developed algorithm, we identified many transcription factors, epigenetic regulators, and long intergenic noncoding RNAs that are cyclically expressed. In addition, a number of these genes also showed circadian expression in mouse tissues. Furthermore, the knockdown of one such factor, Zfp28, influenced the core clock network. Mathematical modeling was able to predict putative regulator-effector interactions between the identified circadian genes and may help for investigations into the gene regulatory networks underlying circadian rhythms.O rganisms adapt to the 24-h day-night cycle, which leads to oscillations in physiology and behavior. This is coordinated by an intrinsic molecular clock originating from the interplay of transcriptional-translational feedback loops (1). In mammals, the core loop consists of the transcriptional activators Clock and Bmal1 and the repressors Period (Per) and cryptochrome (Cry). In a second loop, retinoid-related orphan receptors (ROR) activate transcription while Rev-Erb factors (Nr1d1 and Nr1d2) repress transcription (2). These core clock components also regulate the expression of additional genes, possibly resulting in an oscillating transcription of these socalled clock-controlled genes and finally in the circadian phenotype.Recent genome-wide studies of circadian time courses in various mouse tissues indicated that each tissue expresses its own particular set of cyclical genes, which only partly overlap each other (3-7). Nearly half of all genes in the mouse genome show circadian oscillation in at least one tissue (7). The basic mechanisms causing transcriptional rhythms of the core clock components are similar among all tissues, but how tissue-specific circadian output is achieved remains unknown, although several mechanisms have been proposed (2). Among these are the use of tissue-specific transcription factors (TFs) or coregulators (6,8) and different temporal control of RNA polymerase II recruitment (9, 10), as well as defined rhythms in histone modifications accompanied by differential gene regulation (9-19).To gain further insight into the transcriptional control of the circadian rhythm, we aimed to identify novel factors, particularly transcription factors and epigenetic regula...

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Gene Model 129 (Gm129) Encodes a Novel Transcriptional Repressor That Modulates Circadian Gene Expression

Cited by 58 publications

References 36 publications

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock

Identifying Novel Transcriptional Regulators with Circadian Expression

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