Expression Patterns of Clock Gene mRNAs and Clock Proteins in Human Psoriatic Skin Samples

Psoriasis is a systemic inflammatory skin disorder that can be associated with sleep disturbance and negatively influence the daily rhythm. The link between the pathomechanism of psoriasis and the circadian rhythm has been suggested by several previous studies. However, there are insufficient data on altered clock mechanisms in psoriasis to prove these theories. Therefore, we investigated the expression of the core clock genes in human psoriatic lesional and non-lesional skin and in human adult low calcium temperature (HaCaT) keratinocytes after stimulation with pro-inflammatory cytokines. Furthermore, we examined the clock proteins in skin biopsies from psoriatic patients by immunohistochemistry. We found that the clock gene transcripts were elevated in psoriatic lesions, especially in non-lesional psoriatic areas, except for rev-erbα, which was consistently downregulated in the psoriatic samples. In addition, the REV-ERBα protein showed a different epidermal distribution in non-lesional skin than in healthy skin. In cytokine-treated HaCaT cells, changes in the amplitude of the bmal1, cry1, rev-erbα and per1 mRNA oscillation were observed, especially after TNFα stimulation. In conclusion, in our study a perturbation of clock gene transcripts was observed in uninvolved and lesional psoriatic areas compared to healthy skin. These alterations may serve as therapeutic targets and facilitate the development of chronotherapeutic strategies in the future.

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LC-MS/MS analysis of lesional and normally looking psoriatic skin reveals significant changes in protein metabolism and RNA processing

10.1101/2020.10.07.329540 ◽

2020 ◽

Author(s):

V.V. Sobolev ◽

R.H. Ziganshin ◽

A.V. Mezentsev ◽

A.G. Soboleva ◽

M. Denieva ◽

...

Keyword(s):

Healthy Volunteers ◽

Rna Processing ◽

Protein Identification ◽

Expression Patterns ◽

Differentially Expressed ◽

Psoriatic Skin ◽

Differentially Expressed Proteins ◽

Kinin System ◽

Lesional Skin ◽

Kallikrein Kinin System

AbstractBackgroundPlaque psoriasis is a chronic autoimmune disorder characterized by the development of red scaly plaques. To date psoriasis lesional skin transcriptome has been extensively studied, whereas only few proteomic studies of psoriatic skin are available.AimThe aim of this study was to compare protein expression patterns of lesional and normally looking skin of psoriasis patients with skin of the healthy volunteers, reveal differentially expressed proteins and identify changes in cell metabolism caused by the disease.MethodsSkin samples of normally looking and lesional skin donated by psoriasis patients (n = 5) and samples of healthy skin donated by volunteers (n = 5) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). After protein identification and data processing, the set of differentially expressed proteins was subjected to protein ontology analysis to characterize changes in biological processes, cell components and molecular functions in the patients’ skin compared to skin of the healthy volunteers.ResultsThe performed analysis identified 405 and 59 differentially expressed proteins in lesional and normally looking psoriatic skin compared to healthy control. We discovered decreased expression of KNG1, APOE, HRG, THBS1 and PLG in normally looking skin of the patients. Presumably, these changes were needed to protect the epidermis from spontaneous activation of kallikrein-kinin system and delay the following development of inflammatory response. In lesional skin, we identified several large groups of proteins with coordinated expression. Mainly, these proteins were involved in different aspects of protein and RNA metabolism, namely ATP synthesis and consumption; intracellular trafficking of membrane-bound vesicles, pre-RNA processing, translation, chaperoning and degradation in proteasomes/immunoproteasomes.ConclusionOur findings explain the molecular basis of metabolic changes caused by disease in skin lesions, such as faster cell turnover and higher metabolic rate. They also indicate on downregulation of kallikrein-kinin system in normally looking skin of the patients that would be needed to delay exacerbation of the disease. Data are available via ProteomeXchange with identifier PXD021673.

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Decreased expression of the clock gene Bmal1 is involved in the pathogenesis of temporal lobe epilepsy

Molecular Brain ◽

10.1186/s13041-021-00824-4 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Hao Wu ◽

Yong Liu ◽

Lishuo Liu ◽

Qiang Meng ◽

Changwang Du ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Clock Gene ◽

High Throughput Sequencing ◽

Clock Genes ◽

Hippocampal Sclerosis ◽

Control Group ◽

Type I ◽

Sequencing Analysis ◽

Clock Proteins

AbstractClock genes not only regulate the circadian rhythm of physiological activities but also participate in the pathogenesis of many diseases. Previous studies have documented the abnormal expression of clock genes in epilepsy. However, the molecular mechanism of brain and muscle Arnt-like protein 1 (Bmal1), one of the core clock genes, in the epileptogenesis and seizures of temporal lobe epilepsy (TLE) remain unclear. We first investigated the levels of Bmal1 and other clock proteins in the hippocampus of subjects with epilepsy to define the function of Bmal1. The levels of Bmal1 were decreased during the latent and chronic phases in the experimental group compared with those in the control group. Knockout of Bmal1 in hippocampal dentate gyrus (DG) neurons of Bmal1flox/flox mice by Synapsin 1 (Syn1) promoter AAV (adeno-associated virus) lowered the threshold of seizures induced by pilocarpine administration. High-throughput sequencing analysis showed that PCDH19 (protocadherin 19), a gene associated with epilepsy, was regulated by Bmal1. PCDH19 expression was also decreased in the hippocampus of epileptic mice. Furthermore, the higher levels of Bmal1 and PCDH19 were detected in patients with no hippocampal sclerosis (no HS) than in patients with HS International League Against Epilepsy (ILAE) type I and III. Altogether, these data suggest that decreased expression of clock gene Bmal1 may participate in epileptogenesis and seizures via PCDH19 in TLE.

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Accurate timekeeping is controlled by a cycling activator in Arabidopsis

eLife ◽

10.7554/elife.00473 ◽

2013 ◽

Vol 2 ◽

Cited By ~ 79

Author(s):

Polly Yingshan Hsu ◽

Upendra K Devisetty ◽

Stacey L Harmer

Keyword(s):

Regulatory Network ◽

Clock Gene ◽

Regulatory Mechanism ◽

Clock Genes ◽

Feedback Loops ◽

Transcriptional Repressors ◽

Gene Transcripts ◽

And Control ◽

Complex Regulatory Network ◽

Transcriptional Feedback

Transcriptional feedback loops are key to circadian clock function in many organisms. Current models of the Arabidopsis circadian network consist of several coupled feedback loops composed almost exclusively of transcriptional repressors. Indeed, a central regulatory mechanism is the repression of evening-phased clock genes via the binding of morning-phased Myb-like repressors to evening element (EE) promoter motifs. We now demonstrate that a related Myb-like protein, REVEILLE8 (RVE8), is a direct transcriptional activator of EE-containing clock and output genes. Loss of RVE8 and its close homologs causes a delay and reduction in levels of evening-phased clock gene transcripts and significant lengthening of clock pace. Our data suggest a substantially revised model of the circadian oscillator, with a clock-regulated activator essential both for clock progression and control of clock outputs. Further, our work suggests that the plant clock consists of a highly interconnected, complex regulatory network rather than of coupled morning and evening feedback loops.

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Comparison of expression patterns of six canonical clock genes of follicular phase and luteal phase in Small-tailed Han sheep

Archives Animal Breeding ◽

10.5194/aab-64-457-2021 ◽

2021 ◽

Vol 64 (2) ◽

pp. 457-466

Author(s):

Qi Han ◽

Xiaoyun He ◽

Ran Di ◽

Mingxing Chu

Keyword(s):

Gene Expression ◽

Estrous Cycle ◽

Luteal Phase ◽

Clock Gene ◽

Clock Genes ◽

Expression Patterns ◽

Mrna Levels ◽

Clock Gene Expression ◽

The Relationship ◽

The Brain

Abstract. The circadian rhythm is a biological rhythm that is closely related to the rhythmic expression of a series of clock genes. Results from several studies have indicated that clock genes are associated with the estrous cycle in female animals. Until now, the relationship between estrus cycle transition and clock gene expression in reproductive-axis-related tissues has remained unknown in Small-tailed Han (STH) sheep. This study was conducted to analyze the expression patterns of six canonical clock genes (Clock, BMAL1, Per1, Per2, Cry1, and Cry2) in the follicle phase and luteal phase of STH sheep. We found that all six genes were expressed in the brain, cerebellum, hypothalamus, pituitary, ovary, uterus, and oviduct in follicle and luteal phases. The results indicated that Clock expression was significantly higher in the cerebellum, hypothalamus, and uterus of the luteal phase than that of the follicle phase, whereas BMAL1 expression was significantly higher in the hypothalamus of the luteal phase than that of the follicle phase. Per1 expression was significantly higher in the brain, cerebellum, hypothalamus, and pituitary of the luteal phase than that of the follicle phase, and Per2 expression was significantly higher in the hypothalamus, pituitary, and uterus of the luteal phase than that of the follicle phase. Cry1 expression was significantly higher in the brain, cerebellum, and hypothalamus of the luteal phase than that of the follicle phase, whereas Cry2 expression was significantly higher in the pituitary of the luteal phase than that of the follicle phase. The clock gene expression in all tissues was different between follicle and luteal phases, but all clock gene mRNA levels were found to exhibit higher expression among seven tissues in the luteal phase. Our results suggest that estrous cycles may be associated with clock gene expression in the STH sheep. This is the first study to systematically analyze the expression patterns of clock genes of different estrous cycle in ewes, which could form a basis for further studies to develop the relationship between clock genes and the estrous cycle.

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Decreased Clock Gene Bmal1 Mediates Epileptogenesis via PCDH19 in Temporal Lobe Epilepsy

10.21203/rs.3.rs-133644/v1 ◽

2020 ◽

Author(s):

Hao Wu ◽

Yong Liu ◽

Lishuo Liu ◽

Qiang Meng ◽

Changwang Du ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Clock Gene ◽

High Throughput Sequencing ◽

Clock Genes ◽

Hippocampal Sclerosis ◽

Control Group ◽

Type I ◽

Sequencing Analysis ◽

Clock Proteins

Abstract Clock genes not only regulate the circadian rhythm of physiological activities but also participate in the pathogenesis of many diseases. Previous studies have found the abnormal expression of clock genes in epilepsy. However, as the core clock gene, the molecular mechanism of Bmal1 in the epileptogenesis and seizures of temporal lobe epilepsy (TLE) is still unclear. To define the function of Bmal1, we firstly investigated the levels of Bmal1 and other clock proteins in the hippocampus in epilepsy. In the latency and chronic phases, the levels of Bmal1 were decreased compared with the control group. Knockout of Bmal1 in hippocampal dentate gyrus (DG) neurons of Bmal1flox/flox mice by Synapsin 1 (Syn1) promoter AAV (adeno-associated virus) lowered the threshold of seizures induced by pilocarpine administration. High throughput sequencing analysis showed that PCDH19 (protocadherin 19), a gene associated with epilepsy, was regulated by Bmal1. And the expression of PCDH19 was also decreased in the hippocampus of epileptic mice. Furthermore, the levels of Bmal1 and PCDH19 were higher in the patients with no hippocampal sclerosis (no HS), compared to HS International League Against Epilepsy (ILAE) type I and III. Altogether, these data suggest that decreased expression of clock gene Bmal1 may participate in the epileptogenesis and seizures via PCDH19 in TLE.

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High-throughput RNA sequencing from paired lesional- and non-lesional skin reveals major alterations in the psoriasis circRNAome

BMC Medical Genomics ◽

10.1186/s12920-019-0616-2 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 9

Author(s):

Liviu-Ionut Moldovan ◽

Thomas Birkballe Hansen ◽

Morten Trillingsgaard Venø ◽

Trine Line Hauge Okholm ◽

Thomas Levin Andersen ◽

...

Keyword(s):

Rna Sequencing ◽

High Throughput ◽

Mirna Expression ◽

Binding Sites ◽

Expression Patterns ◽

Psoriatic Skin ◽

Altered Expression ◽

Lesional Skin ◽

Inflammatory Skin ◽

Laser Capture

Abstract Background Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes. It is one of the most prevalent chronic inflammatory skin conditions in adults worldwide, with a considerable negative impact on quality of life. Circular RNAs (circRNAs) are a recently identified type of non-coding RNA with diverse cellular functions related to their exceptional stability. In particular, some circRNAs can bind and regulate microRNAs (miRNAs), a group of RNAs that play a role in the pathogenesis of psoriasis. The aim of this study was to characterize the circRNAome in psoriasis and to assess potential correlations to miRNA expression patterns. Methods We used high-throughput RNA-sequencing (RNA-seq), NanoString nCounter technology and RNA chromogenic in situ hybridization (CISH) to profile the circRNA expression in paired lesional and non-lesional psoriatic skin from patients with psoriasis vulgaris. In addition, 799 miRNAs were profiled using NanoString nCounter technology and laser capture microdissection was used to study the dermis and epidermis separately. Results We found a substantial down-regulation of circRNA expression in lesional skin compared to non-lesional skin. We observed that this mainly applies to the epidermis by analyzing laser capture microdissected tissues. We also found that the majority of the circRNAs were downregulated independently of their corresponding linear host genes. The observed downregulation of circRNAs in psoriasis was neither due to altered expression levels of factors known to affect circRNA biogenesis, nor because lesional skin contained an increased number of inflammatory cells such as lymphocytes. Finally, we observed that the overall differences in available miRNA binding sites on the circRNAs between lesional and non-lesional skin did not correlate with differences in miRNA expression patterns. Conclusions We have performed the first genome-wide circRNA profiling of paired lesional and non-lesional skin from patients with psoriasis and revealed that circRNAs are much less abundant in the lesional samples. Whether this is a cause or a consequence of the disease remains to be revealed, however, we found no evidence that the loss of miRNA binding sites on the circRNAs could explain differences in miRNA expression between lesional and non-lesional skin.

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LC-MS/MS analysis of lesional and normally looking psoriatic skin reveals significant changes in protein metabolism and RNA processing

PLoS ONE ◽

10.1371/journal.pone.0240956 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0240956

Author(s):

V. V. Sobolev ◽

A. V. Mezentsev ◽

R. H. Ziganshin ◽

A. G. Soboleva ◽

M. Denieva ◽

...

Keyword(s):

Healthy Volunteers ◽

Rna Processing ◽

Protein Identification ◽

Expression Patterns ◽

Differentially Expressed ◽

Psoriatic Skin ◽

Differentially Expressed Proteins ◽

Kinin System ◽

Lesional Skin ◽

Kallikrein Kinin System

Background Plaque psoriasis is a chronic autoimmune disorder characterized by the development of red scaly plaques. To date psoriasis lesional skin transcriptome has been extensively studied, whereas only few proteomic studies of psoriatic skin are available. Aim The aim of this study was to compare protein expression patterns of lesional and normally looking skin of psoriasis patients with skin of the healthy volunteers, reveal differentially expressed proteins and identify changes in cell metabolism caused by the disease. Methods Skin samples of normally looking and lesional skin donated by psoriasis patients (n = 5) and samples of healthy skin donated by volunteers (n = 5) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). After protein identification and data processing, the set of differentially expressed proteins was subjected to protein ontology analysis to characterize changes in biological processes, cell components and molecular functions in the patients’ skin compared to skin of the healthy volunteers. The expression of selected differentially expressed proteins was validated by ELISA and immunohistochemistry. Results The performed analysis identified 405 and 59 differentially expressed proteins in lesional and normally looking psoriatic skin compared to healthy control. In normally looking skin of the patients, we discovered decreased expression of KNG1, APOE, HRG, THBS1 and PLG. Presumably, these changes were needed to protect the epidermis from spontaneous activation of kallikrein-kinin system and delay the following development of inflammatory response. In lesional skin, we identified several large groups of proteins with coordinated expression. Mainly, these proteins were involved in different aspects of protein and RNA metabolism, namely ATP synthesis and consumption; intracellular trafficking of membrane-bound vesicles, pre-RNA processing, translation, chaperoning and degradation in proteasomes/immunoproteasomes. Conclusion Our findings explain the molecular basis of metabolic changes caused by disease in skin lesions, such as faster cell turnover and higher metabolic rate. They also indicate on downregulation of kallikrein-kinin system in normally looking skin of the patients that would be needed to delay exacerbation of the disease. Data are available via ProteomeXchange with identifier PXD021673.

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Diversified regulation of circadian clock gene expression following whole genome duplication

10.1101/2020.03.22.002162 ◽

2020 ◽

Author(s):

Alexander C. West ◽

Marianne Iversen ◽

Even H. Jørgensen ◽

Simen R. Sandve ◽

David G. Hazlerigg ◽

...

Keyword(s):

Gene Expression ◽

Whole Genome Duplication ◽

Clock Gene ◽

Genome Duplication ◽

Clock Genes ◽

Expression Patterns ◽

Whole Genome ◽

Functional Diversification ◽

Clock Gene Expression ◽

Multiple Copies

AbstractAcross taxa, circadian control of physiology and behavior arises from cell-autonomous oscillations in gene expression, governed by a networks of so-called ‘clock genes’, collectively forming transcription-translation feedback loops. In modern vertebrates, these networks contain multiple copies of clock gene family members, which arose through whole genome duplication (WGD) events during evolutionary history. It remains unclear to what extent multiple copies of clock gene family members are functionally redundant or have allowed for functional diversification. We addressed this problem through an analysis of clock gene expression in the Atlantic salmon, a representative of the salmonids, a group which has undergone at least 4 rounds of WGD since the base of the vertebrate lineage, giving an unusually large complement of clock genes. By comparing expression patterns across multiple tissues, and during development, we present evidence for gene- and tissue-specific divergence in expression patterns, consistent with functional diversification of clock gene duplicates. In contrast to mammals, we found no evidence for coupling between cortisol and circadian gene expression, but cortisol mediated non-circadian regulated expression of a subset of clock genes in the salmon gill was evident. This regulation is linked to changes in gill function necessary for the transition from fresh- to sea-water in anadromous fish. Overall, this analysis emphasises the potential for a richly diversified clock gene network to serve a mixture of circadian and non-circadian functions in vertebrate groups with complex genomes.Author SummaryThe generation of daily (circadian) rhythms in behaviour and physiology depends on the activities of networks of so-called clock genes. In vertebrates, these have become highly complex due to a process known as whole genome duplication, which has occurred repeatedly during evolutionary history, giving rise to additional copies of key elements of the clock gene network. It remains unclear whether this results in functional redundancy, or whether it has permitted new roles for clock genes to emerge. Here, based on studies in the Atlantic salmon, a species with an unusually large complement of clock genes, we present evidence in favour of the latter scenario. We observe marked tissue-specific, and developmentally-dependent differences in the expression patterns of duplicated copies of key clock genes, and we identify a subset of clock genes whose expression is associated with the physiological preparation to migrate to sea, but is independent of circadian regulation. Associated with this, cortisol secretion is uncoupled from circadian organisation, contrasting with the situation in mammals. Our results indicate that whole genome duplication has permitted clock genes to diversify into non-circadian functions, and raise interesting questions about the ubiquity of mammal-like coupling between circadian and endocrine function.

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Altered expression patterns of clock gene mRNAs and clock proteins in human skin tumors

Tumor Biology ◽

10.1007/s13277-012-0611-0 ◽

2012 ◽

Vol 34 (2) ◽

pp. 811-819 ◽

Cited By ~ 29

Author(s):

Zsuzsanna Lengyel ◽

Csenge Lovig ◽

Siri Kommedal ◽

Rita Keszthelyi ◽

György Szekeres ◽

...

Keyword(s):

Human Skin ◽

Clock Gene ◽

Expression Patterns ◽

Skin Tumors ◽

Altered Expression ◽

Clock Proteins

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Insights into the heat-responsive transcriptional network of tomato contrasting genotypes

Plant Genetic Resources ◽

10.1017/s1479262121000083 ◽

2021 ◽

Vol 19 (1) ◽

pp. 44-57

Author(s):

Sirine Werghi ◽

Charfeddine Gharsallah ◽

Nishi Kant Bhardwaj ◽

Hatem Fakhfakh ◽

Faten Gorsane

Keyword(s):

Heat Stress ◽

Heat Shock ◽

Candidate Genes ◽

Expression Patterns ◽

Response Strategies ◽

Transcriptional Reprogramming ◽

Genes Encoding ◽

Breeding Programmes ◽

Gene Transcripts ◽

Resource Data

AbstractDuring recent decades, global warming has intensified, altering crop growth, development and survival. To overcome changes in their environment, plants undergo transcriptional reprogramming to activate stress response strategies/pathways. To evaluate the genetic bases of the response to heat stress, Conserved DNA-derived Polymorphism (CDDP) markers were applied across tomato genome of eight cultivars. Despite scattered genotypes, cluster analysis allowed two neighbouring panels to be discriminate. Tomato CDDP-genotypic and visual phenotypic assortment permitted the selection of two contrasting heat-tolerant and heat-sensitive cultivars. Further analysis explored differential expression in transcript levels of genes, encoding heat shock transcription factors (HSFs, HsfA1, HsfA2, HsfB1), members of the heat shock protein (HSP) family (HSP101, HSP17, HSP90) and ascorbate peroxidase (APX) enzymes (APX1, APX2). Based on discriminating CDDP-markers, a protein functional network was built allowing prediction of candidate genes and their regulating miRNA. Expression patterns analysis revealed that miR156d and miR397 were heat-responsive showing a typical inverse relation with the abundance of their target gene transcripts. Heat stress is inducing a set of candidate genes, whose expression seems to be modulated through a complex regulatory network. Integrating genetic resource data is required for identifying valuable tomato genotypes that can be considered in marker-assisted breeding programmes to improve tomato heat tolerance.

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