ChIP-Seq Analysis of Histone Modifications at the Core of the Arabidopsis Circadian Clock

AbstractA distinct 12-hour clock exists in addition to the 24-hour circadian clock to coordinate metabolic and stress rhythms. Here, we show that liver-specific ablation of X-box binding protein 1 (XBP1) disrupts the hepatic 12-hour clock and promotes spontaneous non-alcoholic fatty liver disease (NAFLD). We show that hepatic XBP1 predominantly regulates the 12-hour rhythmicity of gene transcription in the mouse liver and demonstrate that perturbation of the 12-hour clock, but not the core circadian clock, is associated with the onset and progression of this NAFLD phenotype. Mechanistically, we provide evidence that the spliced form of XBP1 (XBP1s) binds to the hepatic 12-hour cistrome to directly regulate the 12-hour clock, with a periodicity paralleling the harmonic activation of the 12-hour oscillatory transcription of many rate-limiting metabolic genes known to have perturbations in human metabolic disease. Functionally, we show that Xbp1 ablation significantly reduces cellular membrane fluidity and impairs lipid homeostasis via rate-limiting metabolic processes in fatty acid monounsaturated and phospholipid remodeling pathways. These findings reveal that genetic disruption of the hepatic 12-hour clock links to the onset and progression of NAFLD development via transcriptional regulator XBP1, and demonstrate a role for XBP1 and the 12-hour clock in the modulation of phospholipid composition and the maintenance of lipid homeostasis.

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Achilles-Mediated and Sex-Specific Regulation of Circadian mRNA Rhythms in Drosophila

Journal of Biological Rhythms ◽

10.1177/0748730419830845 ◽

2019 ◽

Vol 34 (2) ◽

pp. 131-143 ◽

Cited By ~ 3

Author(s):

Jiajia Li ◽

Renee Yin Yu ◽

Farida Emran ◽

Brian E. Chen ◽

Michael E. Hughes

Keyword(s):

Circadian Clock ◽

Molecular Mechanisms ◽

Rna Binding ◽

Clock Genes ◽

Peripheral Tissues ◽

Knock Down ◽

Rhythmic Expression ◽

The Core ◽

Physiological Processes ◽

Specific Regulation

The circadian clock is an evolutionarily conserved mechanism that generates the rhythmic expression of downstream genes. The core circadian clock drives the expression of clock-controlled genes, which in turn play critical roles in carrying out many rhythmic physiological processes. Nevertheless, the molecular mechanisms by which clock output genes orchestrate rhythmic signals from the brain to peripheral tissues are largely unknown. Here we explored the role of one rhythmic gene, Achilles, in regulating the rhythmic transcriptome in the fly head. Achilles is a clock-controlled gene in Drosophila that encodes a putative RNA-binding protein. Achilles expression is found in neurons throughout the fly brain using fluorescence in situ hybridization (FISH), and legacy data suggest it is not expressed in core clock neurons. Together, these observations argue against a role for Achilles in regulating the core clock. To assess its impact on circadian mRNA rhythms, we performed RNA sequencing (RNAseq) to compare the rhythmic transcriptomes of control flies and those with diminished Achilles expression in all neurons. Consistent with previous studies, we observe dramatic upregulation of immune response genes upon knock-down of Achilles. Furthermore, many circadian mRNAs lose their rhythmicity in Achilles knock-down flies, suggesting that a subset of the rhythmic transcriptome is regulated either directly or indirectly by Achilles. These Achilles-mediated rhythms are observed in genes involved in immune function and in neuronal signaling, including Prosap, Nemy and Jhl-21. A comparison of RNAseq data from control flies reveals that only 42.7% of clock-controlled genes in the fly brain are rhythmic in both males and females. As mRNA rhythms of core clock genes are largely invariant between the sexes, this observation suggests that sex-specific mechanisms are an important, and heretofore under-appreciated, regulator of the rhythmic transcriptome.

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KaiC from a cyanobacterium Gloeocapsa sp. PCC 7428 retains functional and structural properties required as the core of circadian clock system

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2019.03.051 ◽

2019 ◽

Vol 131 ◽

pp. 67-73 ◽

Cited By ~ 4

Author(s):

Atsushi Mukaiyama ◽

Dongyan Ouyang ◽

Yoshihiko Furuike ◽

Shuji Akiyama

Keyword(s):

Circadian Clock ◽

Structural Properties ◽

The Core ◽

Clock System

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Intrinsic disorder is an essential characteristic of components in the conserved circadian circuit

Cell Communication and Signaling ◽

10.1186/s12964-020-00658-y ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 1

Author(s):

Jacqueline F. Pelham ◽

Jay C. Dunlap ◽

Jennifer M. Hurley

Keyword(s):

Circadian Clock ◽

Neurospora Crassa ◽

Mus Musculus ◽

Intrinsically Disordered Proteins ◽

Intrinsic Disorder ◽

Cellular Systems ◽

Disordered Proteins ◽

Circadian Timing ◽

Intrinsically Disordered ◽

The Core

Abstract Introduction The circadian circuit, a roughly 24 h molecular feedback loop, or clock, is conserved from bacteria to animals and allows for enhanced organismal survival by facilitating the anticipation of the day/night cycle. With circadian regulation reportedly impacting as high as 80% of protein coding genes in higher eukaryotes, the protein-based circadian clock broadly regulates physiology and behavior. Due to the extensive interconnection between the clock and other cellular systems, chronic disruption of these molecular rhythms leads to a decrease in organismal fitness as well as an increase of disease rates in humans. Importantly, recent research has demonstrated that proteins comprising the circadian clock network display a significant amount of intrinsic disorder. Main body In this work, we focus on the extent of intrinsic disorder in the circadian clock and its potential mechanistic role in circadian timing. We highlight the conservation of disorder by quantifying the extent of computationally-predicted protein disorder in the core clock of the key eukaryotic circadian model organisms Drosophila melanogaster, Neurospora crassa, and Mus musculus. We further examine previously published work, as well as feature novel experimental evidence, demonstrating that the core negative arm circadian period drivers FREQUENCY (Neurospora crassa) and PERIOD-2 (PER2) (Mus musculus), possess biochemical characteristics of intrinsically disordered proteins. Finally, we discuss the potential contributions of the inherent biophysical principals of intrinsically disordered proteins that may explain the vital mechanistic roles they play in the clock to drive their broad evolutionary conservation in circadian timekeeping. Conclusion The pervasive conservation of disorder amongst the clock in the crown eukaryotes suggests that disorder is essential for optimal circadian timing from fungi to animals, providing vital homeostatic cellular maintenance and coordinating organismal physiology across phylogenetic kingdoms. Graphical abstract

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SWI/SNF remains localized to chromatin in the presence of SCHLAP1

10.1101/322065 ◽

2018 ◽

Cited By ~ 1

Author(s):

Jesse R. Raab ◽

Keriayn N. Smith ◽

Camarie C. Spear ◽

Carl J. Manner ◽

J. Mauro Calabrese ◽

...

Keyword(s):

Prostate Cancer ◽

Chromatin Remodeling ◽

Histone Modifications ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Metastatic Prostate Cancer ◽

The Core ◽

Prostate Cells ◽

Chromatin Remodeling Complex ◽

Non Coding Rnas

AbstractSCHLAP1 is a long-noncoding RNA that is prognostic for progression to metastatic prostate cancer and promotes an invasive phenotype. SCHLAP1 is reported to function by depleting the core SWI/SNF subunit, SMARCB1, from the genome. SWI/SNF is a large, multi-subunit, chromatin remodeling complex that can be combinatorially assembled to yield hundreds to thousands of distinct complexes. Here, we investigated the hypothesis that SCHLAP1 affects only specific forms of SWI/SNF and that the remaining SWI/SNF complexes were important for the increased invasion in SCHLAP1 expressing prostate cells. Using several assays we found that SWI/SNF is not depleted from the genome by SCHLAP1 expression. We find that SCHLAP1 induces changes to chromatin openness but is not sufficient to drive changes in histone modifications. Additionally, we show that SWI/SNF binds many coding and non-coding RNAs. Together these results suggest that SCHLAP1 has roles independent of canonical SWI/SNF and that SWI/SNF broadly interacts with RNA.

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Physcion Protects Against Ethanol-Induced Liver Injury by Reprogramming of Circadian Clock

Frontiers in Pharmacology ◽

10.3389/fphar.2020.573074 ◽

2020 ◽

Vol 11 ◽

Author(s):

Youli Yao ◽

Along Zuo ◽

Qiyu Deng ◽

Shikang Liu ◽

Tianying Zhan ◽

...

Keyword(s):

Liver Injury ◽

Circadian Clock ◽

Hepg2 Cells ◽

Treatment Options ◽

Potential Contribution ◽

Protective Agent ◽

Protective Effects ◽

The Core ◽

Metabolic Genes

The circadian clock plays a key role in our daily physiology and metabolism. Alcohol consumption disrupts the circadian rhythm of metabolic genes in the liver; however, the potential contribution of circadian clock modulation to alcoholic liver disease (ALD) is unknown. We identified a novel liver protective agent, physcion, which can alleviate fat accumulation and inflammation in ALD mice via reprogramming the hepatic circadian clock. The model of alcoholic hepatitis was established by intragastrically administering ethanol. In vitro, physcion was investigated by treating HepG2 cells with ethanol. The role of circadian clock in Physcion caused liver protection was tested by knocking down the core circadian gene Bmal1. Physcion application caused reduced lipogenesis and alleviated inflammation in alcohol-induced mice. In alcoholic hepatosteatosis models, physcion upregulated the core circadian genes. And the circadian misalignment triggered by ethanol was efficiently reversed by physcion. Physcion attenuated lipogenesis via reprogramming the circadian clock in HepG2 cells. Suppression of Bmal1 by RNA interference abolished the protective of physcion. In addition, Physcion binds to the active pocket of BMAL1 and promotes its expression. The study identified the novel liver protective effects of physcion on alcohol-induced liver injury, and modulation of the core circadian clock regulators contributes to ALD alleviation. More importantly, strategies targeting the circadian machinery, for example, Bmal1, may prove to be beneficial treatment options for this condition.

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